Delayed release deferiprone tablets and methods of using the same

ABSTRACT

The invention is directed to pharmaceutical compositions such as tablets that exhibit delayed release properties when administered as either whole or half tablets. The invention is also directed to delayed release tablets comprising deferiprone for oral administration, for which twice daily administration is bioequivalent to the same daily dose of an immediate release tablet administered thrice daily. The invention is also directed to methods of making and using the same.

REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 17/327,135, filed on May 21, 2021, which is a continuation ofU.S. patent application Ser. No. 16/714,520, filed on Dec. 13, 2019,which is a continuation of U.S. patent application Ser. No. 16/171,170,filed on Oct. 25, 2018, which claims priority to U.S. ProvisionalApplication Nos. 62/577,055, filed on Oct. 25,2017, and 62/596,043,filed on Dec. 7, 2017, each of which is incorporated herein by referencein its entirety.

BACKGROUND

Deferiprone is an iron chelator, used in the treatment of generalizediron overload, particularly in conditions where frequent bloodtransfusions lead to iron overload including, e.g., thalassemia (RenzoGalanello, Ther Clin Risk Manag. 2007 Oct;3(5):795-805), Sickle CellDisease (Ware and Kwiatkowski, Pediatr Clin North Am. 2013Dec;60(6):1393-406) and Myelodysplasia (Sheth, Curr Opin Hematol. 2014May;21(3):179-85) (each incorporated herein by reference in itsentirety). Deferiprone is also used in conditions of localized tissue orcellular iron overload, even in the absence of generalized ironoverload, such as neurodegenerative diseases where cellular ironmishandling is a prominent feature including, e.g., Friedreich's Ataxia,Parkinson's disease, Pantothenate Kinase-Associated Neurodegeneration(PKAN) and other forms of neurodegeneration with brain iron accumulation(NBIA), Multiple Sclerosis, Age-Related Macular Degeneration andSuperficial Siderosis. See Kakhlon et al., Can J Physiol Pharmacol. 2010Mar;88(3):187-96, Cabantchik et al., Front Pharmacol. 2013 Dec;4:167,Cossu et al., Parkinsonism. Relat Disord., 2014 Jun;20(6):651-4, Weigelet al., ASN Neuro. 2014 Jan;6(1), Song et al., Free Radic Biol Med. 2012Jul;53(1):64-71, and Levy and Llinas, Stroke. 2012 Jan;43(1):120-4 (eachincorporated herein by reference in its entirety).

Deferiprone is sold in the U.S. and elsewhere as an Immediate Release(IR) 500 mg tablet, for example, under the trade name Ferriprox®, whichis also available as an IR 1000 mg tablet and a liquid formulation of100 mg/mL in some jurisdictions.

BRIEF SUMMARY

Certain aspects of this disclosure are directed to a delayed releasetablet comprising deferiprone for oral administration to a humansubject, wherein twice daily administration of the delayed releasetablet is bioequivalent in the steady state to the same daily dose of animmediate release tablet comprising deferiprone administered three timesdaily.

In another aspect, the disclosure is directed to a tablet for oraladministration of an active pharmaceutical ingredient (in particular,deferiprone) to a human subject, wherein the tablet comprises: (a) acore comprising the active pharmaceutical ingredient in atherapeutically effective amount and an enteric polymer, and (b) anenteric coating, wherein the tablet is scored such that it can beadministered as a whole tablet or a half tablet and wherein if thetablet is administered as one or more half tablets, the half tablets arebioequivalent to the whole in, e.g., a single dose study, in a fastedstate, a fed state, or both.

In another aspect, the disclosure is directed to a tablet for oraladministration of an active pharmaceutical ingredient comprising: (a) acore comprising the active pharmaceutical ingredient in atherapeutically effective amount and an enteric polymer, and (b) anenteric coating, the tablet being scored to facilitate breakage intohalf tablets, wherein both the whole and the half tablets display adelayed release dissolution profile.

In another aspect, the disclosure is directed to a tablet for oraladministration comprising: (a) a core comprising deferiprone in atherapeutically effective amount and an enteric polymer; and (b) anenteric coating comprising an enteric polymer, wherein the tablet issuitable for twice daily dosing.

In another aspect, the disclosure is directed to a tablet comprisingdeferiprone for twice daily oral administration to a human subject,wherein a single dose of the tablet provides a mean AUC_(∞)/C_(max)ratio between 3.5 hours and 6.0 hours in both fasted and fed state.

In another aspect, the disclosure is directed to a tablet for oraladministration comprising: (a) a core comprising 1000 mg or 600 mg ofdeferiprone, an enteric polymer, a pH adjusting agent, a glidant, and alubricant; and (b) an enteric coating comprising a plasticizer, adiluent, an anti-tacking agent, and an enteric polymer, the tablet beinga whole tablet which is scored to facilitate breakage of the tablet intohalf tablets.

In another aspect, the disclosure is directed to a method for treating asubject with iron overload or a neurodegenerative disease (e.g.,Huntington's disease or amyotrophic lateral sclerosis), comprisingorally administering to the subject in need thereof a deferiprone tablet(e.g., a delayed release tablet) disclosed herein.

In certain aspects, the disclosure is directed to a method of treatingHuntington's disease in a subject in need thereof comprisingadministering a composition comprising deferiprone to the subject.

In certain aspects, the disclosure is directed to a method of treatingamyotrophic lateral sclerosis (ALS) in a subject in need thereofcomprising administering a composition comprising deferiprone to thesubject. Some embodiments are directed to methods of reducing or slowingthe progression of a disability associated with ALS. In someembodiments, the subject is further administered riluzole.

In certain aspects, the disclosure is to directed to a method oftreating a human subject with iron overload comprising orallyadministering to the subject in need thereof 3000 mg/day deferiprone,wherein the subject is administered the deferiprone two times per day.

In certain aspects, the disclosure is to directed to a method oftreating a human subject with iron overload comprising orallyadministering to the subject in need thereof 1200 mg/day deferiprone,wherein the subject is administered the deferiprone two times per day.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the dissolution of whole and half delayed release (DR)tablets in 0.1N HCl, reflecting dissolution in stomach acid.

FIG. 2 shows the dissolution of whole and half DR tablets in pH 6.8,reflecting dissolution in the jejunum and ileum.

FIG. 3 shows the dissolution of whole and half DR tablets in pH 4.5,reflecting dissolution in the duodenum.

FIG. 4 shows mean serum concentration profiles of deferiprone DR andimmediate release (IR) tablets.

DESCRIPTION OF THE INVENTION I. Definitions

As used herein, the indefinite articles “a” or “an” should be understoodto refer to “one or more” of any recited or enumerated component. Forexample, “a tablet” refers to one or more tablets.

Also as used herein, “and/or” refers to and encompasses any and allpossible combinations of one or more of the associated listed items, aswell as the lack of combinations when interpreted in the alternative(“or”).

When the term “about” is used in conjunction with a numerical value orrange, it modifies that value or range by extending the boundaries aboveand below the numerical values set forth. The term “about” is usedherein to modify a numerical value above and below the stated value by avariance of 10 percent, up or down (higher or lower), i.e., ±10%, unlessa different variance is indicated (e.g., ±30%, ±20%, ±5%, ±1%, etc.).

Wherever aspects are described herein with the language “comprising,”otherwise analogous aspects described in terms of “consisting of” and/or“consisting essentially of” are also provided. To the extent that theterm “includes” or “including” is used in the specification or theclaims, it is intended to be inclusive in a manner similar to the term“comprising” as that term is interpreted when employed as a transitionalword in a claim.

“Deferiprone” as used herein refers to deferiprone or a pharmaceuticalacceptable salt thereof.

The term “pharmaceutically acceptable salt” of a given compound refersto salts that retain the biological effectiveness and properties of thegiven compound, and which are not biologically or otherwise undesirable.“Pharmaceutically acceptable salts” include, for example, salts withinorganic acids and salts with an organic acid. Salts of deferiprone caninclude pharmaceutically acceptable salts, especially salts with bases,such as appropriate alkali metal or alkaline earth metal salts, e.g.,sodium, potassium or magnesium salts, pharmaceutically acceptabletransition metal salts, such as zinc salts, or salts with organicamines, such as cyclic amines, such as mono-, di- or tri-loweralkylamines, such as hydroxy-lower alkylamines, e.g., mono-, di- ortrihydroxy-lower alkylamines, hydroxy-lower alkyl-lower alkylamines orpolyhydroxy-lower alkylamines. Cyclic amines are, e.g., morpholine,thiomorpholine, piperidine or pyrrolidine. Suitable mono-loweralkylamines are, e.g., ethyl- and tert-butylamine; di-lower alkylaminesare, e.g., diethyl- and diisopropylamine; and tri-lower alkylamines are,e.g. trimethyl- and triethylamine. Appropriate hydroxy-lower alkylaminesare, e.g., mono-, di- and triethanolamine; hydroxy-lower alkyl-loweralkylamines are, e.g., N,N-dimethylamino- and N,N-diethylaminoethanol; asuitable polyhydroxy-lower alkylamine is, e.g., glucosamine.

“Core” or “tablet core” as used herein comprises an active ingredient,e.g., deferiprone, and one or more excipients compressed into anuncoated tablet. The core can be coated with various coatings, includingan enteric coating.

“Delayed release” or “DR” as used herein refers to protecting an activeingredient, e.g., deferiprone, from rapid release at acidic pH, e.g., inthe stomach at least in the fasted state, while enabling the activeingredient to be released at a higher rate at a higher pH, e.g., in theintestines. In some embodiments, DR will be understood to mean that,when tested in USP apparatus 2 at 75 rpm, the extent of dissolution willbe under 20% at 1 hour in 0.1N HCl, and the rate of dissolution will besubstantially higher (e.g., over 30%, e.g. over 40%, in 1 hour) inphosphate buffer with pH 6.8 than the rate of dissolution in 0.1N HCl.

“Disintegrant” as used herein refers to an excipient that is insolublein water, but swells when wetted to cause a tablet to disintegrate.

“Dissolution” as used herein refers to the process by which a soluteforms a solution in a solvent.

“Enteric coat” or “enteric coating” as used herein refers to a coatingcomprising an enteric polymer. An enteric coating can serve to preventor delay a tablet's dissolution or disintegration in a gastricenvironment.

“Enteric coated tablet” means a tablet having a core comprising anactive ingredient, which is coated with an enteric coating.

“Enteric polymer” as used herein is understood to mean a polymer that isrelatively insoluble at the acidic pH of the fasted stomach (e.g., aboutpH 1 to about pH 4), but soluble at higher pH (e.g., about pH 4.5 toabout pH 8), which corresponds to the pH in the small intestine orthereafter, particularly in the duodenum or ileum.

“Fasted state” as used herein refers to abstinence from food for adefined period of time after a meal (typically, at least several hours,e.g., 4 or 6 hours, after a meal).

“Fed state” as used herein refers to administration with a meal or soonafter a meal (e.g., within about 1 hour).

“Gastric distress” as used herein refers to discomfort of thegastrointestinal (GI) tract, e.g., one or more of pain, cramping,bloating, nausea, indigestion, heartburn, and gas.

“Half tablet” as used herein means either of the two parts of a tabletobtained by splitting the tablet into two parts of equal orapproximately equal weight. In some embodiments, a half tablet is fromabout 40% to about 60% by weight of the whole tablet from which the halfwas derived. In some embodiments, the approximately equal weight of eachhalf tablet is about 45-55% of the total weight of the whole tablet.

“Percent” or “%” as used herein refers to weight percentage (w/w) unlessotherwise specified.

“Scored tablet” as used herein refers to a tablet that is debossed withone or more lines, also known as a “score line”, to facilitate splittingthe tablet, e.g., to enable administration of a half tablet. In someembodiments, the tablet can be scored with two, three, four, or morescore lines.

“Tablet” as used herein refers a solid oral pharmaceutical dosage form.In some embodiments, the tablet is a compressed tablet.

“Whole tablet” means a complete tablet, i.e., not broken or split intoparts.

Terms such as “treating” or “treatment” or “to treat” or “ameliorating”or “alleviating” or “to alleviate” can refer to both 1) therapeuticmeasures that cure, slow down, lessen symptoms of, reverse, and/or haltprogression of a diagnosed pathologic condition or disorder and 2)prophylactic or preventative measures that prevent, reduce the incidenceof, reduce the risk of, and/or slow the development of a targetedpathologic condition or disorder. Thus, those in need of treatmentinclude those who already have the disorder; those prone to developingthe disorder; and those in whom the disorder is to be prevented.Beneficial or desired clinical results include, but are not limited to,alleviation of symptoms, diminishment of extent of disease, stabilized(i.e., not worsening) state of disease, delay or slowing of diseaseprogression, amelioration or palliation of the disease state, andremission (whether partial or total), whether detectable orundetectable. “Treatment” can also mean prolonging survival as comparedto expected survival if not receiving treatment. Those in need oftreatment include those who already have the condition or disorder aswell as those prone to developing the condition or disorder or those inwhich the condition or disorder is to be prevented or incidence reduced.

By “subject” or “individual” or “patient,” is meant any human subject,for whom diagnosis, prognosis, treatment, or therapy is desired.

By “therapeutically effective dose or amount” or “effective amount” isintended an amount of active pharmaceutical ingredient, e.g.,deferiprone, that when administered brings about a positive therapeuticresponse with respect to treatment of or reducing the risk of a diseasein a subject to be treated.

It will be understood that the deferiprone IR tablets used as the“reference” or “reference product” herein are Ferriprox® IR tablets (500mg) as approved by FDA and sold in the United States. For instance, the“reference” or “reference product” herein may be a Ferriprox® IR tabletwith (1) a core containing 500 mg deferiprone, microcrystallinecellulose, colloidal silicon dioxide, and magnesium stearate; and (2) acoating containing hydroxypropyl methyl cellulose, polyethylene glycol,and titanium dioxide.

II. Tablets

In certain aspects, the application is directed to a delayed releasetablet comprising deferiprone in its core. Delayed release, e.g.,provided by enteric coating, serves to delay dissolution of an activeingredient, e.g., deferiprone, from a tablet core. In some embodiments,delayed release is desirable either in the case of a medicinalingredient that causes gastric irritation if released in the fastedstomach, and/or in the case of a medicinal ingredient that is acidlabile and would thus degrade if released in the fasted stomach.

Some pharmaceutical tablets for oral administration are coated with anenteric coat to provide delayed release. Some other pharmaceuticaltablets for oral administration are debossed with a score line, to makeit easy for the patient to break the tablets into two approximatelyequal parts to enable administration of half tablets, e.g., for dosingflexibility. However, it is difficult to combine both features into asingle tablet; that is, to produce a tablet that is enteric coated butcan be broken into two parts without destroying the delayed releasefeature. This is because the surface at the interface of a broken tabletis no longer protected by the enteric coating. This results in at leastthe following problems: (1) If the unprotected core disintegrates and/ordissolves quickly, the dissolution of the broken tablet in the stomachacid will be faster than the whole tablet, so that protection againstgastric irritation will be lost; (2) Alternatively, if the unprotectedcore tablet disintegrates and/or dissolves slowly enough to preventgastric irritation even without the protection of the enteric coating,then dissolution and absorption in the intestines can also be relativelyslow, causing a reduction of extent of absorption and/or peak serumlevels; and (3) The broken tablet no longer delivers the drug at thesame rate and possibly the same extent as the unbroken tablet. Theseproblems can contribute to half tablets not being bioequivalent to wholetablets. For example, Iranian patent application 90-07-27-71996discloses a formulation of deferiprone that is enteric coated. Itdiscloses protecting against gastric distress by using a methacrylicacid copolymer to enteric-coat the deferiprone tablet, wherein thecoating is about 7.4% of the total weight of the tablet (800 mg coretablet containing 500 mg of deferiprone). The enteric coated tabletformulation disclosed in Iranian patent application 90-07-27-71996 losesthe enteric coating benefit when the tablets are bisected or halved. TheEC tablet from Iranian patent application 90-07-27-71996 (Avicenna Lab)included a core tablet of 500 mg deferiprone, 290 mg microcrystallinecellulose, 1 mg colloidal silicon dioxide, and 9 mg magnesium stearate(800 mg total core weight); and a coating of 34.68 mg methacrylic acidcopolymer, 15.56 mg talc, 3.61 mg PEG 6000, 4.38 mg titanium dioxide,4.93 mg hypromellose, 6 cm Poaz, and 0.82 mg sodium bicarbonate (63.98mg total weight of coating). The weight of the coating is about 7.4% ofthe total weight of the EC tablet. In certain embodiments, the tabletsof the current application differ from the EC tablet from Iranian patentapplication 90-07-27-71996. For example, in some embodiments, the DRtablets disclosed herein do not include 290 mg microcrystallinecellulose, 1 mg colloidal silicon dioxide, and/or 9 mg magnesiumstearate (800 mg total core weight); and some embodiments, the coatingof the DR tablets disclosed herein do not include 34.68 mg methacrylicacid copolymer, 15.56 mg talc, 3.61 mg PEG 6000, 4.38 mg titaniumdioxide, 4.93 mg hypromellose, 6 cm Poaz, and/or 0.82 mg sodiumbicarbonate (63.98 mg total weight of coating). Furthermore, in certainembodiments, the weight of the coating of the DR tablets disclosedherein is not about 7.4% of the total weight of the EC tablet.

In certain aspects, the present disclosure is directed to a composition,e.g., a tablet, comprising deferiprone for oral administration to ahuman subject. In one embodiment, the composition is a tablet for oraladministration comprising (a) a core comprising deferiprone and (b) anenteric coating. Preferably, the tablet is designed to releasedeferiprone in the post-stomach portions of the gastrointestinal (GI)tract. In some embodiments, the tablet does not substantiallydisintegrate in the stomach or at least in the fasted stomach, i.e., thetablet substantially does not dissolve until the tablet reaches theintestine. In some embodiments, at least 75%, at least 80%, at least85%, at least 95%, at least 99%, or 100% of the tablet disintegrates inthe intestine.

In some embodiments, the tablet is administered as a whole tablet. Insome embodiments, the tablet is scored for administration of about halfthe dosage of the whole tablet. In some embodiments, the tablet isadministered as a half tablet. In some embodiments, the tablet isadministered as one or more whole tablets in combination with one ormore half tablets.

In certain aspects, a tablet of the present disclosure is formulated tohave relatively little (e.g., less than 20%), if any, dissolution in thefasted stomach, but will more rapidly dissolve in the intestines, andthus can be referred to as a delayed release composition. In someembodiments, a tablet of the present disclosure confers a similar rateof dissolution with half and whole tablets, independent of the pH of thedissolving media. In some aspects, a tablet of the present disclosureembraces the attributes of an enteric coated tablet, without itsdeficiencies, so that tablets can be halved, to enable fine tuning ofthe dosing to administer whole tablets, half tablets or any combinationthereof. Half tablets of the disclosure resist dissolution in acidicmedia (0.1 N HCl), representing the fasted stomach contents, as do wholetablets; and, at a higher pH, representing the contents of the smallintestine, also exhibit a rate of dissolution similar to whole tablets.

In some embodiments, the enteric coating is between about 1-20%, 1-15%,1-10%, about 1-9%, about 1-8%, about 1-7%, about 1-6%, about 1-5%, about1-4%, about 1-3%, about 1-2%, about 0.5-5%, or about 0.5-2% of the totalweight of the tablet. In some embodiments, the coating is less than 7%,less than 6%, less than 5%, less than 4%, less than 3%, less than 2.5%,less than 2.4%, less than 2.3%, less than 2.2.%, less than 2.1% or lessthan 2% of the total weight of the tablet; and/or the coating is morethan 1% of the total weight of the tablet. In some embodiments, thecoating is about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%,about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2.0%,about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%,about 2.7%, about 2.8%, about 2.9%, or about 3.0%, or a range betweenany two of the preceding values, e.g., 1.0-1.8%, 1.0-2.0%, 1.0-2.4%,1.2-1.7%, 1.5-2.0%, 2.0-2.5%, 2.2-2.7%, or 2.5-3.0% of the total weightof the tablet. In some embodiments, the coating is about 1.5% of thetotal weight of the tablet. In other embodiments, the coating is about2.5% of the total weight of the tablet.

III. Core

The present disclosure is directed to a composition, e.g., a delayedrelease tablet, comprising a core comprising an active pharmaceuticalingredient, e.g., deferiprone or a pharmaceutically acceptable saltthereof.

In some embodiments, the tablet core comprises between about 100 mg toabout 1500 mg, between about 250 mg to about 1250 mg, or between about900 mg to about 1100 mg of deferiprone. In some embodiments, the tabletcomprises about 100 mg, about 200, about 250 mg, about 300 mg, about 400mg, about 500 mg, about 600 mg, about 700 mg, about 750 mg, about 800mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about1300 mg, about 1400 mg, or about 1500 mg of deferiprone. In certainembodiments, the tablet comprises about 1000 mg of deferiprone.

In some embodiments, the active pharmaceutical ingredient, e.g.,deferiprone, is about 75-95% (e.g., 80-95% or 85-95%) of the total coreweight. In some embodiments, the active agent, e.g., deferiprone, isabout 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about91%, about 92%, about 93%, about 94%, or about 95% of the total coreweight.

In some embodiments, the tablet core of one DR tablet for once, twice,or three times daily dosing comprises at least about 200 mg, at leastabout 300 mg, at least about 400 mg, at least about 500 mg, or at leastabout 600 mg of deferiprone. In some embodiments, the tablet core of oneDR tablet for once, twice, or three times daily dosing comprises atleast about 600 mg of deferiprone. In some embodiments, the tablet coreof one DR tablet for once, twice, or three times daily dosing comprisesat least about 500 mg of deferiprone. In some embodiments, the tabletcore comprises between about 200 mg to about 1500 mg, about 300 mg toabout 900 mg, about 300 mg to about 700 mg, about 500 mg to about 700mg, about 500 mg to 1500 mg, about 500 mg to 750 mg, about 900 mg toabout 1100 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg,about 750 mg, about 800 mg, about 1000 mg, about 1200 mg, about 1250 mg,or about 1500 mg of deferiprone. In some embodiments, tablet corescomprising 600 mg or 1000 mg of deferiprone are preferred.

In some embodiments, the tablet core of one DR tablet for once, twice,or three times daily dosing comprises at least about 200 mg, at leastabout 300 mg, or at least about 400 mg of deferiprone. In someembodiments, the tablet core of one DR tablet for once, twice, or threetimes daily dosing comprises about 200 mg to about 500 mg, about 200 mgto about 400 mg, about 200 mg, about 300 mg, about 400 mg, or about 500mg of deferiprone. In some embodiments, the tablet core of one DR tabletfor twice daily dosing comprises at least about 500 mg of deferiprone.In some embodiments, the tablet core comprises between about 200 mg toabout 1500 mg, about 300 mg to about 900 mg, about 300 mg to about 600mg, about 300 mg to about 500 mg, about 500 mg to 1500 mg, about 500 mgto 750 mg, about 900 mg to about 1100 mg, about 600 mg, about 750 mg,about 800 mg, about 1000 mg, about 1200 mg, about 1250 mg, or about 1500mg of deferiprone.

In some embodiments, the tablet core comprises an enteric polymer as anexcipient. Prior to the present application, when an enteric coatedtablet was broken, e.g., in half at the score line, the surface at theinterface of the broken score line, e.g., of the two halves, was nolonger protected by the enteric coating. In some embodiments, includingan enteric polymer in the core helps maintain a relatively lowdissolution rate in 0.1 N HCl for a split tablet, e.g., a half tablet,thus limiting dissolution in the fasted stomach, while still enablingfaster dissolution at intestinal pH.

In some embodiments, the enteric polymer is between about 1% to 20%, 1%to 15%, 1% to 10%, or 1% to 5% by weight of the core. In someembodiments, the enteric polymer is about 1%, about 1.5%, about 2%,about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about5.5%, about 6%, about 6.5%, or about 7% by weight of the core, or arange between any two of the preceding values, e.g., about 2-2.5%,2.5-3%, 3-3.5%, 3.5-4%, 4-4.5%, or 4.5-5% by weight of the core. In someembodiments, the enteric polymer is about 2.5% by weight of the core. Insome embodiments, the enteric polymer is about 4.5% by weight of thecore.

In some embodiments, the enteric polymer in the core is selected fromthe group consisting of hydroxypropyl methylcellulose (HPMC), acetatesuccinate (i.e., HPMCAS), HPMC phthalate, polyvinyl acetate phthalate,methacrylic acid copolymers, a derivative thereof, and a combinationthereof. In some embodiments, the enteric polymer in the core is HPMCAS.

In some embodiments, the tablet core of a tablet, e.g., a delayedrelease tablet, disclosed herein includes between about 900 mg to about1100 mg of deferiprone and between about 10 mg to about 80 mg, betweenabout 20 mg to about 80 mg, between about 20 mg to about 60 mg, betweenabout 20 mg to about 50 mg, between about 20 mg to about 40 mg, betweenabout 25 mg to about 35 mg of an enteric polymer, e.g., HPMCAS. In someembodiments, the tablet core of a tablet, e.g., a delayed releasetablet, disclosed herein includes between about 500 mg to about 750 mgof deferiprone and between about 10 mg to about 80 mg, between about 20mg to about 80 mg, between about 20 mg to about 60 mg, between about 20mg to about 50 mg, between about 20 mg to about 40 mg, between about 25mg to about 35 mg of an enteric polymer, e.g., HPMCAS. In someembodiments, the tablet core of a tablet, e.g., a delayed releasetablet, disclosed herein includes between about 400 mg to about 800 mgof deferiprone (e.g., about 600 mg) and between about 10 mg to about 80mg, between about 20 mg to about 80 mg, between about 20 mg to about 60mg, between about 20 mg to about 50 mg, between about 20 mg to about 40mg, or between about 25 mg to about 35 mg of an enteric polymer, e.g.,HPMCAS.

In some embodiments, the tablet core of a tablet, e.g., a delayedrelease tablet, disclosed herein includes between about 200 mg to about500 mg of deferiprone and between about 10 mg to about 80 mg, betweenabout 20 mg to about 80 mg, between about 20 mg to about 60 mg, betweenabout 20 mg to about 50 mg, between about 20 mg to about 40 mg, betweenabout 25 mg to about 35 mg of an enteric polymer, e.g., HPMCAS.

In some embodiments, the tablet core of a tablet, e.g., a delayedrelease tablet, disclosed herein includes about 1000 mg of deferiproneand about 30 mg of an enteric polymer, e.g., HPMCAS. In particular, thetablet core of the tablet includes 1000 mg of deferiprone and 28.5 mg ofHPMCAS.

In some embodiments, the tablet core of a tablet, e.g., a delayedrelease tablet, disclosed herein includes about 600 mg of deferiproneand about 30 mg of an enteric polymer, e.g., HPMCAS. In particular, thetablet core of the tablet includes 600 mg of deferiprone and 29.5 mg ofHPMCAS.

In some embodiments, the tablet core of a tablet, e.g., a delayedrelease tablet, disclosed herein includes between about 400 mg ofdeferiprone and about 20 to about 30 mg of an enteric polymer, e.g.,HPMCAS. In some embodiments, the tablet core of a tablet, e.g., adelayed release tablet, disclosed herein includes about 600 mg ofdeferiprone and about 20 mg to about 30 mg of an enteric polymer, e.g.,HPMCAS.

In some embodiments, the core comprises one or more basic excipients. Insome embodiments, the basic excipient is selected from the groupconsisting of meglumine, metal oxides, metal hydroxides, basic salts ofweak acids, and a combination thereof. Metal oxides include, but are notlimited to, magnesium oxide, aluminum oxide, and zinc oxide. Metalhydroxides include, but are not limited to, sodium hydroxide, potassiumhydroxide, magnesium hydroxide, and calcium hydroxide. Basic salts ofweak acids include, but are not limited to, sodium or potassium salts ofcarbonate, bicarbonate, acetate, and citrate. In certain embodiments,the basic excipient is magnesium oxide, meglumine or a combinationthereof. In some embodiments, the basic excipient is magnesium oxide.

In some embodiments, the basic excipient is about 1-10%, about 1-5%,about 1-4%, about 2-8%, about 2-6%, about 2-5%, about 2-4%, about 3-5%,about 3-4%, or about 4-5% of the total weight of the core. In someembodiments, the tablet core of a tablet, e.g., a delayed releasetablet, disclosed herein includes magnesium oxide in an amount of about3%, about 4%, or about 5% of the total weight of the core. In someembodiments, the basic excipient is about 4.5% of the total weight ofthe core. In some embodiments, the basic excipient is about 3.7% of thetotal weight of the core.

In some embodiments, the tablet core of a tablet, e.g., a delayedrelease tablet, disclosed herein comprises about 5 mg, 10 mg, 15 mg, 20mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70mg, 75 mg, 80 mg, 90 mg, or 100 mg of a basic excipient, or a rangebetween any two of the preceding values, e.g., about 5-100 mg, 5-80 mg,10-60 mg, 40-60 mg, or 20-30 mg of a basic excipient.

In some embodiments, the tablet core of a tablet, e.g., a delayedrelease tablet, disclosed herein includes about 1000 mg of deferiproneand about 50 mg of a basic excipient, e.g., magnesium oxide. In someembodiments, the tablet core of a tablet, e.g., a delayed releasetablet, disclosed herein includes about 600 mg of deferiprone and about25 mg of a basic excipient, e.g., magnesium oxide. In some embodiments,the tablet core of a tablet, e.g., a delayed release tablet, disclosedherein includes about 400 mg of deferiprone and about 10 to about 20 mgof a basic excipient, e.g., magnesium oxide.

In some embodiments, the tablet core does not comprise a disintegrant.

In some embodiments, the tablet core is coated with an enteric coatingdescribed herein. In some embodiments, the core comprises the same or adifferent enteric polymer than the enteric polymer in the coating.

In some embodiments, the core is at least 90%, at least 91%, at least92%, at least 93%, at least 94%, at least 95%, at least 96%, at least97%, at least 98%, or at least 99% of total tablet weight.

In some embodiments, other excipients included in the tablet core areselected from fillers, binders (e.g., to increase tablet hardness),lubricants such as magnesium stearate (e.g., to prevent sticking to thetooling during compression into tablets), glidants such as colloidalsilicon dioxide (e.g., to improve flow in the tableting process), andcombinations thereof.

In some embodiments, the core comprises a glidant such as, for example,colloidal silicon dioxide. In some embodiments, the glidant is about 1%,0.5%, 0.45, 0.4%, 0.35%, 0.3%, 0.25%, 0.2%, 0.1% by weight of the core,or a range between any two of the preceding values, e.g., about0.2-0.5%, 0.2-0.4%, 0.2-0.3%, 0.3-0.5%, 0.3-0.4%, or 0.4-0.5% by weightof the core. In some embodiments, the core comprises about 0.45% byweight of a glidant (e.g., colloidal silicon dioxide). In someembodiments, the core comprises about 0.3% by weight of a glidant (e.g.,colloidal silicon dioxide).

In some embodiments, the tablet core of a tablet, e.g., a delayedrelease tablet, disclosed herein includes about 1000 mg of deferiproneand about 5 mg of a glidant, e.g., colloidal silicon dioxide. In someembodiments, the tablet core of a tablet, e.g., a delayed releasetablet, disclosed herein includes about 600 mg of deferiprone and about2 mg of a glidant, e.g., colloidal silicon dioxide. In some embodiments,the tablet core of a tablet, e.g., a delayed release tablet, disclosedherein includes about 400 mg of deferiprone and about 1 mg to about 2 mgof a glidant, e.g., colloidal silicon dioxide.

In some embodiments, the core comprises a lubricant such as, forexample, magnesium stearate, calcium stearate, stearic acid, sodiumstearyl fumarate, or talc. In some embodiment, the core comprisesmagnesium stearate as a lubricant.

In some embodiments, the lubricant is about 0.5%, 0.6%, 0.7%, 0.8%,0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, or 2% byweight of the core, or a range between any two of the preceding values,e.g., 0.5-1%, 0.5-2%, 0.6-2%, 0.7-2%, 1-1.5%, 1.2-1.7%, or 1.5-2% byweight of the core. In some embodiments, the core comprises about 0.6%by weight of a lubricant (e.g., magnesium stearate). In someembodiments, the core comprises about 1.5% by weight of a lubricant(e.g., magnesium stearate).

In some embodiments, the tablet core of a tablet, e.g., a delayedrelease tablet, disclosed herein comprises about 2 mg, 3 mg, 4 mg, 5 mg,7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17mg, 18 mg, 19 mg, 21 mg, 22 mg, 23 mg, 24 mg, or 25 mg of a lubricant,or a range between any two of the preceding values, e.g., about 2-25 mg,2-10 mg, 2-8 mg, 2-6 mg, 7-20 mg, 10-20 mg, or 15-20 mg of a lubricant.

In some embodiments, the tablet core of a tablet, e.g., a delayedrelease tablet, disclosed herein includes about 1000 mg of deferiproneand about 17 mg of a lubricant, e.g., magnesium stearate. In someembodiments, the tablet core of a tablet, e.g., a delayed releasetablet, disclosed herein includes about 600 mg of deferiprone and about4 mg of a lubricant, e.g., magnesium stearate. In some embodiments, thetablet core of a tablet, e.g., a delayed release tablet, disclosedherein includes about 400 mg of deferiprone and about 1 mg to about 4 mgof a lubricant, e.g., magnesium stearate.

In some embodiments, the core comprises HPMC acetate succinate,magnesium oxide, colloidal silicon dioxide, magnesium stearate, andabout 1000 mg of deferiprone.

In some embodiments, the core comprises HPMC acetate succinate,magnesium oxide, colloidal silicon dioxide, magnesium stearate, andabout 600 mg of deferiprone.

In some embodiments, the core comprises HPMC acetate succinate,magnesium oxide, colloidal silicon dioxide, magnesium stearate, andabout 400 mg of deferiprone.

IV. Enteric Coating

In certain aspects of the disclosure, the composition, e.g., a tablet,can comprise an enteric coating. Such a coating can serve to reducegastric irritation. The enteric coating can delay the dissolution fromthe tablets core until the tablet reaches the intestine. The presentdisclosure is directed to a composition, e.g., a delayed release tablet,comprising a core comprising an active pharmaceutical ingredient, e.g.,deferiprone or a pharmaceutically acceptable salt thereof, and anenteric coating.

Suitable enteric polymers for the enteric coating include, e.g.,hydroxypropyl methylcellulose acetate succinate (also referred to ashypromellose acetate succinate or HPMCAS), HPMC phthalate (also referredto as hypromellose phthalate), polyvinyl acetate phthalate, celluloseacetate phthalate, cellulose acetate trimellitate, shellac, zein,methacrylic acid copolymers (e.g., methacrylic acid copolymer Type CDispersion 30%), derivatives thereof, and combinations thereof.

In some embodiments, the preferred enteric polymers in the entericcoating are HPMC acetate succinate and methacrylic acid copolymers,e.g., methacrylic acid copolymer type C in aqueous dispersion.

In some embodiments, the enteric polymer in the coating is about 0.5%,0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%,1.8%, 1.9%, 2%, 2.5%, 3%, 3.5%, or 4%, by weight of the tablet, or arange between any two of the preceding values, e.g., 0.5-1%, 0.5-2%,0.5-3%, 0.5-4%, 0.6-1%, 0.6-2%, 0.6-3%, 0.6-4%, 0.7-1%, 0.7-2%, 0.7-3%,0.7-4%, 1-1.5%, 1.1-1.7%, 1-2%, 1.5-2%, 1-3%, 1-3.5%, or 1-4%, by weightof the tablet. In some embodiments, the enteric polymer in the coating(e.g., methacrylic acid copolymer) is about 0.8% by weight of tablet. Insome embodiments, the enteric polymer in the coating (e.g., methacrylicacid copolymer) is about 1.4% by weight of the tablet (e.g., methacrylicacid copolymer).

In some embodiments, the enteric coating comprises about 5 mg, 5.5 mg, 6mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 11 mg, 12mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 25 mg, or 30mg of an enteric polymer, or a range between any two of the precedingvalues, e.g. about 5-20 mg, 7-20 mg, 7-30 mg, 8-15 mg, or 8-10 mg of anenteric polymer.

In some embodiments, a tablet, e.g., a delayed release DR tablet,disclosed herein includes about 1000 mg of deferiprone and about 9 mg ofan enteric polymer in the coating, e.g., methacrylic acid copolymer(from about 31 mg of dispersion). In some embodiments, the tablet coreof a tablet, e.g., a delayed release tablet, disclosed herein includesabout 600 mg of deferiprone and about 9 mg of an enteric polymer in thecoating, e.g., methacrylic acid copolymer (from about 31 mg ofdispersion). In some embodiments, the tablet core of a tablet, e.g., adelayed release tablet, disclosed herein includes about 400 mg ofdeferiprone and about 9 mg of an enteric polymer in the coating, e.g.,methacrylic acid copolymer (from about 31 mg of dispersion).

In some embodiments, the enteric coating comprises, in addition to theenteric polymer, other excipients, including for example, a plasticizer,a lubricant or anti-tack agent such as talc, an opacifier, a colorant, adiluent, or any combination thereof.

In some embodiments, the enteric coating plasticizer is diethylphthalate, citrate esters (e.g., triethyl citrate), polyethylene glycol,glycerol, acetylated glycerides, acetylated citrate esters, dibutylsebecate, castor oil, or any combination thereof.

In some embodiments, the enteric coating comprises about 0.5 mg, 0.6 mg,0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 2mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, or 5 mg of a plasticizer, or arange between any two of the preceding values, e.g. about 0.5-5 mg,0.7-2 mg, or 0.8-1.2 mg of a plasticizer.

In some embodiments, the enteric coating comprises a diluent (e.g.,lactose, sucrose, fructose, mannitol, and the like, or combinationsthereof). In some embodiments, the enteric coating comprises talc as thelubricant or anti-tack agent.

Certain aspects of the application are directed to a composition (e.g.,delayed release tablet) comprising a core comprises 1000 mg ofdeferiprone, an enteric polymer, a pH adjusting agent, a glidant, and alubricant; and a coating comprises a plasticizer, a diluent, ananti-tacking agent, and an enteric polymer. In some embodiments, thecore comprises 1000 mg of deferiprone, HPMCAS-LF, Magnesium oxide,Colloidal Silicon Dioxide, Magnesium stearate; and the coating comprisesTriethyl Citrate, Sucrose, Talc, and Methacrylic Acid CopolymerDispersion. In a further embodiment, the composition (e.g., delayedrelease tablet) core comprises 1000 mg of deferiprone, 28 mg HPMCAS-LF,50 mg Magnesium oxide, 4.8 mg (2.6 mg+2.2 mg) Colloidal Silicon Dioxide,17.2 mg Magnesium stearate; and the coating comprises 1.03 mg TriethylCitrate, 3.09 mg Sucrose, 3.09 mg Talc, and 31 mg Methacrylic AcidCopolymer Dispersion.

Certain aspects of the application are directed to a composition (e.g.,delayed release tablet) comprising a core comprises 600 mg ofdeferiprone, an enteric polymer, a pH adjusting agent, a glidant, and alubricant; and a coating comprises a plasticizer, a diluent, ananti-tacking agent, and an enteric polymer. In some embodiments, thecore comprises 600 mg of deferiprone, HPMCAS-LF, Magnesium oxide,Colloidal Silicon Dioxide, and Magnesium stearate; and the coatingcomprises Triethyl Citrate, Sucrose, Talc, and Methacrylic AcidCopolymer Dispersion. In a further embodiment, the core comprises 600 mgof deferiprone, 29.5 mg HPMCAS-LF, 24.5 mg Magnesium oxide, 2 mg (1 mg+1mg) Colloidal Silicon Dioxide, and 4 mg Magnesium stearate; and thecoating comprises 1.03 mg Triethyl Citrate, 3.09 mg Sucrose, 3.09 mgTalc, and 31 mg Methacrylic Acid Copolymer Dispersion.

In some embodiments, the core comprises 600 mg of deferiprone,Hypromellose Acetate Succinate AS-LF, Magnesium oxide light, ColloidalSilicon Dioxide, and Magnesium stearate; and the coating comprisesTriethyl Citrate, Sucrose, Talc, Methacrylic Acid Copolymer Dispersion,and Titanium Dioxide. In a further embodiment, the core comprises 600 mgof deferiprone, 29.5 mg Hypromellose Acetate Succinate AS-LF, 24.5 mgMagnesium oxide light, 2 mg (1 mg+1 mg) Colloidal Silicon Dioxide, and 4mg Magnesium stearate; and the coating comprises 1.032 mg TriethylCitrate, 3.09 mg Sucrose, 2.09 mg Talc, 30.96 mg Methacrylic AcidCopolymer Dispersion, and 8.5 mg Titanium Dioxide.

In some embodiments, the enteric coating is between about 1-20%, 1-15%,1-10%, about 1-9%, about 1-8%, about 1-7%, about 1-6%, about 1-5%, about1-4%, about 1-3%, about 1-2%, about 0.5-5%, or about 0.5-2% of the totalweight of the tablet. In some embodiments, the coating is less than 7%,less than 6%, less than 5%, less than 4%, less than 3% or less than 2%of the total weight of the tablet. In some embodiments, the entericcoating is between 0.5% and 5% of the total tablet weight. In someembodiments, the enteric coating is between 0.5% and 3% of the totaltablet weight. In some embodiments, the enteric coating is between 0.5%and 2% of the total tablet weight. In some embodiments, the entericcoating is between 0.5% and 1.5% of the total tablet weight. In someembodiments, the coating is about 1%, about 1.5%, about 2%, about 2.5%,about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, orabout 6% of the total weight of the tablet.

In some embodiments, the coating is about 1.5% of the total weight ofthe tablet. In some embodiments, the coating is about 2.5% of the totalweight of the tablet.

In some embodiments, a tablet, e.g., a delayed release tablet, disclosedherein includes about 1000 mg of deferiprone and about 1.5% of anenteric coating by weight of the tablet. In some embodiments, a tablet,e.g., a delayed release tablet, disclosed herein includes about 600 mgof deferiprone and about 2.5% of an enteric coating by weight of thetablet.

Another aspect of the disclosure is directed to a method for delayedrelease of deferiprone in a human subject comprising administering atablet of the disclosure to the subject, wherein the tablet comprises acore and an enteric coating as disclosed herein and is administered as awhole tablet, a half tablet, or a combination thereof.

Another aspect of the disclosure is directed to a method for reducinggastric distress in a human subject in need of deferiprone treatmentcomprising administering a tablet of the disclosure to the subject,wherein the tablet comprises a core and an enteric coating as disclosedherein and the tablet is administered as a whole tablet, a half tablet,or a combination thereof.

V. Dosing

The present disclosure provides dosing regimens useful for the methodsof using the pharmaceutical compositions, e.g., delayed release tablets,described herein. In some embodiments, a deferiprone composition of thedisclosure is administered to a subject in need thereof once, twice, orthree times daily. In particular, the deferiprone composition of thedisclosure is administered to a subject in need thereof twice daily.

In some embodiments, the subject in need thereof suffers from ironoverload (e.g., transfusional iron overload, e.g., in subjects sufferingfrom thalassemia, myelodysplasia, or sickle cell disease). In someembodiments, the subject in need thereof suffers from aneurodegenerative disease (e.g., Parkinson's disease, amyotrophiclateral sclerosis (ALS), Huntington's disease, Friedreich's Ataxia,Pantothenate Kinase Associated Neurodegeneration (PKAN), orneurodegeneration with brain iron accumulation (NBIA)).

In some embodiments, the subject in need thereof suffers from ironoverload that is transfusional iron overload. In certain aspects, thesubject suffers from transfusional iron overload and whose priorchelation therapy is inadequate. In certain aspects, the subject suffersfrom transfusion iron overload and has a cardiac MM T2* of 20 ms or less(e.g., 10 ms).

In some embodiments, the pharmaceutical composition is for oraldelivery, e.g., a tablet of the disclosure.

In some aspects, a DR deferiprone composition (in particular, tabletcompositions) of the disclosure is administered twice daily. IRdeferiprone tablets are inconvenient to patients as they require threetimes daily dosing (TID dosing). Patients generally prefer a regimen oftwice daily (BID) or once daily dosing. One reason that TID dosing hasbeen required is that the elimination half-life of deferiprone is onlyabout 2 hours. After a deferiprone IR tablet is ingested, thedeferiprone content is rapidly absorbed from the upper part of thegastrointestinal tract, appearing in the blood within 5 to 10 minutes oforal administration. Peak serum concentrations occur approximately 1hour after a single dose in fasted healthy subjects and patients, and upto 2 hours after a single dose in the fed state. Because the eliminationhalf-life is short, the serum concentration is reduced to belowtherapeutically effective levels well before the next dose, if dosing isless frequent than TID.

Another problem associated with IR deferiprone is acute gastricdistress, which can persist for days or longer. This is a limitingadverse event for a substantial number of patients, e.g., patients whostop taking the medication in the first few days as a result of thegastric distress and thus forego the benefits of deferiprone.

Extended release (ER) dosage forms have been developed to enable twicedaily or once daily dosing for some drugs. Such dosage forms aredesigned to release the active drug content gradually over an extendedperiod of time, usually about 5 to 10 hours for a dosage form intendedfor twice daily dosing, and over about 8 to 20 hours for a dosage formintended for once daily dosing. This can generally be done only fordrugs that are absorbed throughout the ileum and duodenum, so that theextent of absorption is not compromised by the gradual release as thedosage form passes through the intestines.

An issue with ER dosage forms relates to the maximum (or peak) serumconcentration (C_(max)). By protracting the period of absorption, e.g.,with the use of an extended release formulation, the C_(max) will end upmuch lower than with the IR tablet. This could be a problem in achievingthe desired effects of certain drugs, such as iron chelators, where boththe C_(max) and the area under the serum concentration vs. time graph(AUC) can impact the efficacy.

Certain aspects of the present disclosure are directed to a deferipronetablet for twice daily (BID) dosing that is bioequivalent in the steadystate to an IR tablet for TID dosing using the same total daily dosage.In certain embodiments, the BID is bioequivalent in the steady state,wherein after at least three days of dosing, the mean ratio of AUC (over24 hours) and the mean ratio of Cmax for the tablets for BID dosingrelative to the IR tablets for TID is within 80% to 125%. The tabletsfor twice daily dosing then provide the same chelation benefit to asubject as the IR tablets, yet with certain advantages of the twicedaily dosing. In addition to the convenience of BID dosing, this regimenenhances compliance in patients, e.g., those who choose not to bringtheir mid-day dose to school or work and thus lose the benefit of a fulldaily dose of deferiprone.

In certain aspects, the disclosed formulations are utilized to targetparticular serum concentration time profiles and achieve the improvedproperties disclosed herein.

Certain aspects of the disclosure are directed to overcoming problemsassociated with TID dosing, without sacrificing the benefits ofachieving the C_(max), by providing a tablet for twice dailyadministration that provides both of the following when compared to anIR tablet administered TID having the same total daily dosage:

i. Similar extent of absorption as IR tablets, and thus similar averageserum concentration; and

ii. Similar peak serum concentration, but with the peaks occurring twicedaily instead of three times daily.

Certain aspects of the disclosure are directed to overcoming problemsassociated with TID dosing, without sacrificing the benefits ofachieving the C_(max), by providing a tablet for twice dailyadministration that provides both of the following when compared to anIR tablet administered TID having the same total daily dosage:

i. Equivalent extent of absorption as IR tablets, and thus similaraverage serum concentration; and

ii. Equivalent peak serum concentration, but with the peaks occurringtwice daily instead of three times daily.

Another aspect of the present disclosure is to provide a tabletformulation comprising deferiprone for twice daily administration thatexhibits delayed onset of release as well as lengthening the duration ofrelease, but without affecting the terminal half-life, thus enabling theachievement of peaks and troughs in the serum. This advantage is appliedto both whole and half tablets, as the dissolution rate of half tabletsis similar to that of whole tablets at all relevant pHs, so that halftablets are bioequivalent to whole tablets in single dose bioequivalencestudies, in both the fasted state and the fed state.

Results shown herein also demonstrate that in the steady state, thedelayed release tablets of the present disclosure when administered BIDwere able to achieve the same maximum peak concentrations (Cmax) as IRtablets of Ferriprox®, when the IR tablets were given three times a day,and the total amount absorbed (AUC) was the same for both products overa 24 hour period. Thus, certain benefits of twice daily dosing, and insome instances less gastrointestinal distress, are obtained, without acompromise on efficacy.

“Bioequivalence” refers to the absence of a significant differencebetween the bioavailability, i.e., the extent of absorption and peakconcentration, between two pharmaceutical drug products (e.g., a testproduct and a reference product) over the course of a period of time, atthe same dose and under the same conditions.

The determination of whether or not a test product is bioequivalent to areference product is determined by performing a study, referred to as abioequivalence or comparative bioavailability study, in a group ofsubjects, usually about 18-36 subjects or more, under controlledconditions.

The study can be done in a “crossover” design, which means that thestudy is done in 2 or more phases, usually at least a week apart,depending in part on the half-life of the drug. In the first phase, halfthe subjects are randomly assigned to ingest the test product first andthe other half ingest the reference product first. In the second phase,each subject ingests the alternate product.

In each phase, blood samples are drawn from each subject, on apredetermined schedule after ingestion of the test product. The bloodsamples are then analyzed to determine serum concentrations of the drug(test product, e.g., deferiprone) at each time point. The results foreach subject, for both the test and reference products, are thencompiled to determine the following:

-   -   AUC — defined as the area under the curve of serum concentration        versus time for a chosen period of time after ingestion, for        example, 24 hours.    -   AUCT or AUC_(T)—defined as the area under the curve of serum        concentration versus time from the time of ingestion to the last        sampling time.    -   AUCI or AUC_(I)—defined as the area under the curve of serum        concentration versus time from the time of ingestion to time        infinity, which is estimated using AUC_(T) and the terminal        elimination rate.    -   C_(max)—defined as the peak serum concentration.    -   AUC ratio—defined as the ratio of AUC from the test product to        AUC from the reference product, calculated for each subject.    -   C_(max) ratio—defined as the ratio of C_(max) from the test        product to C_(max) from the reference product, also calculated        for each subject.    -   Mean AUC ratio—defined as the antilog of the average of the        logarithms of AUC ratios for all subjects.    -   Mean C_(max) ratio—defined as the antilog of the average of the        logarithms of C_(max) ratios for all subjects.

An “equivalent extent of absorption” is defined as a mean AUC ratiobetween 80% and 125% calculated for a test product versus a referenceproduct, in a study usually conducted in 18 or more subjects.

An “equivalent peak concentration” is defined as a mean C_(max) ratiobetween 80% and 125% calculated for a test product versus a referenceproduct, in a study usually conducted in 18 or more subjects.

Both an equivalent extent of absorption and an equivalent peakconcentration must be achieved to be considered bioequivalent.

For any bioavailability parameter, the “true” mean ratio of theparameter as measured in the test product to that as measured in thereference product is defined as the mean ratio that would be found in astudy in an infinite number of subjects. As no study can be done in aninfinite number of subjects, the mean ratio as determined in any studyis only an estimate of the true mean ratio. As the number of subjects ina study is increased, the mean ratio results generally become a betterestimate of the true mean ratio. Unless stated otherwise herein,reference to a product having a particular ratio of a parameter to thatof a reference product will be understood to mean the mean as determinedin a study in at least 18 subjects.

Bioequivalence studies can be conducted as single dose studies, eitherin the fasted state or the fed state. In a study conducted in the fastedstate, the products are ingested without food and usually at leastseveral hours before or after a meal. If a study is conducted in the fedstate, the products are ingested with a meal or soon after a meal. Insome embodiments, bioequivalence studies can be single-dose or steadystate. In a single dose study, each subject receives only one dose ofthe product being ingested in each phase, although that dose can includemore than 1 tablet, depending on the size of the dose being studied. Ina steady state study, subjects ingest doses on a dosing schedule regimenbeing tested (for example, twice or three times daily) for at leastseveral doses until steady state is reached, and then blood samples aretaken over a predetermined period, usually over one day. For assessmentof modified release formulations, whether delayed release or extendedrelease, a study in the presence of food and following several doses toachieve steady state (to simulate effects during chronic dosing) isoften conducted.

The administration of a tablet to a patient who has recently ingested ameal can alter the rate and extent of absorption and, if a medicine isto be taken with a meal, it can be important to characterize the rateand extent of absorption of the delayed release tablet with food,compared to an IR tablet with food.

Bioequivalence studies can also be conducted as multi-dose studies,conducted over at least several days of dosing to determine whether ornot two products are bioequivalent in the “steady state”, after severaldays of dosing. “Steady state” as used herein is achieved when the rateof drug input equals the rate of drug elimination, as determined by nofurther increase in drug concentrations in the subject following theadministration of repeated doses. “Bioequivalent in the steady state”will be understood to mean that, after at least three days of dosing ofa test product, the mean ratio of AUC (over 24 hours) and the mean ratioof Cmax is within 80% to 125% of those for a reference product.

In some embodiments, the present disclosure provides a composition,e.g., delayed release tablet, for twice daily dosing that isbioequivalent in the steady state to the same daily dose of an IR tablettaken three times daily, e.g., as illustrated in the examples below.

Certain aspects of the disclosure are directed to a tablet for oraladministration comprising deferiprone, for which twice dailyadministration provides equivalent extent of absorption, at least in asteady state study, when compared to the same total daily dosageadministered three times daily as IR tablets.

Certain aspects of the disclosure are directed to a tablet for oraladministration comprising deferiprone, for which twice dailyadministration provides equivalent peak serum concentration, at least ina steady state study, when compared to the same total daily dosageadministered three times daily as IR tablets.

Certain aspects of the disclosure are directed to a tablet for BID oraladministration comprising deferiprone, for which the characteristics ofequivalent extent of absorption and/or rate of absorption, as aforesaid,are met for, not only whole tablets, but also for half tablets, so as toallow dosing with half tablets. In some embodiments, the tablets arepreferably debossed with a score line, to facilitate breaking into halftablets. For example, if a whole tablet comprises about 1000 mg ofdeferiprone, such that a half tablet comprises about 500 mg ofdeferiprone, then a dose of about 1500 mg can be taken as one wholetablet plus one half tablet, and a total daily dose of 3000 mg can beachieved with BID dosing.

In some embodiments, to achieve desired absorption characteristics,tablets of the disclosure are formulated to exhibit desired dissolutionrates as shown by in vitro dissolution testing. References todissolution testing herein can be understood to mean testing in USPapparatus 2, at 75 rpm, in 900 mL of media, i.e., 0.1 N hydrochloricacid (HCl), 0.5 M phosphate buffer at pH 4.5, and 0.5 M phosphate bufferat pH 6.8, unless indicated otherwise. A stated dissolution result isunderstood to mean the average result of 6 or more tablets.

Certain aspects of the disclosure are directed to a half tablet or wholetablet for oral administration to a human subject, comprising a corecomprising deferiprone, for which dissolution at 60 minutes in pH 4.5 isbetween about 55% and about 90%, between about 60% and about 90%, orbetween about 65% and about 85%.

Certain aspects of the disclosure are directed to a half tablet or wholetablet for oral administration to a human subject comprising a corecomprising deferiprone, for which dissolution at 60 minutes in pH 6.8 isbetween about 55% and about 90%, between about 60% and about 90%, orbetween about 65% and about 85%.

In some aspects, approximately 100% of the deferiprone is releasedwithin about 90 minutes when measured by USP Apparatus Type II PaddleMethod at 75 rpm in 900 mL at pH 6.8 or 4.5. In some aspects,approximately 50% of the deferiprone is released within about 30 minuteswhen measured by USP Apparatus Type II Paddle Method at 75 rpm in 900 mLat pH 6.8 or 4.5.

Also, certain aspects of the disclosure are directed to a half tablet orwhole tablet for oral administration to a human subject comprising acore comprising deferiprone, for which dissolution at 60 minutes in 0.1N HCl is under 20%, or under 10%.

In some embodiments, a single dose of a tablet of the disclosureprovides a mean AUC_(∞)/C_(max) ratio between 3.5 hours and 6.0 hours infasted state when the tablet is administered to human subjects.

In some embodiments, a single dose of a tablet of the disclosureprovides a mean AUC_(∞)/C_(max) ratio between 3.5 hours and 6.0 hours infed state when the tablet is administered to human subjects. In someembodiments, the tablet comprises 1000 mg deferiprone. In someembodiments, the tablet comprises 600 mg deferiprone. In someembodiments, the mean C_(max) is between 2.670 and 13.232 μg/mL when thetablet is administered to a human subjects. In some embodiments, themedian T_(max) is between 1.33 and 4.00 hours when the tablet isadministered to human subjects. In some embodiments, the median T_(max)is between 2.00 and 8.00 hours when the tablet is administered to humansubjects. In some embodiments, the median T_(max) is between 1.33 and6.03 hours when the tablet is administered to human subjects. In someembodiments, the ratio of AUC_(I)/C_(max) is between 2.858 to 6.596hours when the tablet is administered to human subjects. In someembodiments, the ratio of AUC_(I)/C_(max) is between 3.225 to 8.506hours when the tablet is administered to human subjects.

In some embodiments, the dosing is for treating a subject suffering fromiron overload (e.g., transfusional iron overload, e.g., in subjectssuffering from thalassemia, myelodysplasia, or sickle cell disease).Certain aspects of the disclosure are directed to dosing regimens usefulfor the methods of treating iron overload as described herein. In someembodiments of the methods for treating iron overload, the total amountof deferiprone administered per day is about 1 mg/kg/day to about 200mg/kg/day, about 1 mg/kg/day to about 150 mg/kg/day, about 20 mg/kg/dayto about 150 mg/kg/day, about 50 mg/kg/day to about 125 mg/kg/day, orabout 50 mg/kg/day to about 100 mg/kg/day. In some embodiments, theadministration is one, twice or three times daily. In some embodiments,the dosing for treatment of iron overload is about 1 mg/kg to about 150mg/kg, about 20 mg/kg to about 150 mg/kg, 25 mg/kg to about 125 mg/kg,or about 50 mg/kg to about 100 mg/kg twice daily (BID).

In some embodiments, the dosing is for treating a subject suffering froma neurodegenerative disease, e.g., Parkinson's disease, amyotrophiclateral sclerosis (ALS), Huntington's disease, Friedreich's Ataxia,Pantothenate Kinase Associated Neurodegeneration (PKAN), orneurodegeneration with brain iron accumulation (NBIA). In someembodiments, a deferiprone composition of the disclosure (IR or DRcomposition) is administered once, twice, or three times daily to asubject suffering from a neurodegenerative disease, e.g., Parkinson'sdisease, ALS, Huntington's disease, Friedreich's Ataxia, PantothenateKinase Associated Neurodegeneration (PKAN), or neurodegeneration withbrain iron accumulation (NBIA). In some embodiments, the subject suffersfrom ALS. In some embodiments, the subject suffers from Huntington'sdisease. In some embodiments, the subject suffers from Parkinson'sdisease.

Certain aspects of the disclosure are directed to dosing regimens usefulfor the methods of treating a neurodegenerative disease describedherein. In some embodiments of the methods for treating aneurodegenerative disease, the total amount of deferiprone administeredper day is about 1 mg/kg/day to about 200 mg/kg/day, about 1 mg/kg/dayto about 150 mg/kg/day, about 1 mg/kg/day to about 100 mg/kg/day, about1 mg/kg/day to about 50 mg/kg/day, about 1 mg/kg/day to about 40mg/kg/day, about 1 mg/kg/day to about 30 mg/kg/day, about 1 mg/kg/day toabout 20 mg/kg/day, about 1 mg/kg/day to about 15 mg/kg/day, about 1mg/kg/day to about 10 mg/kg/day, or about 1 mg/kg/day to about 5mg/kg/day. In some embodiments, the administration is one, twice orthree times daily. In some embodiments, the dosing for treatment of aneurodegenerative disease is about 1 mg/kg to about 100 mg/kg, about 1mg/kg to about 50 mg/kg, 1 mg/kg to about 40 mg/kg, about 1 mg/kg toabout 25 mg/kg, or about 1 mg/kg to about 20 mg/kg two times daily(BID).

In some embodiments of the methods, the amount of deferiprone in thecomposition (e.g., a tablet) is from about 100 mg to about 1500 mg, fromabout 200 mg to about 1500 mg, from about 400 mg to about 1500 mg, fromabout 600 mg to about 1500 mg, from about 800 mg to about 1500 mg, fromabout 1200 mg to about 1500 mg, from about 200 mg to about 1200 mg, fromabout 400 mg to about 1200 mg, from about 600 mg to about 1200 mg, fromabout 800 mg to about 1200 mg, from about 200 mg to about 1000 mg, fromabout 400 mg to about 1000 mg, from about 600 mg to about 1000 mg, fromabout 800 mg to about 1000 mg, from about 200 mg to about 800 mg, fromabout 400 mg to about 800 mg, from about 600 mg to about 800 mg, fromabout 200 mg to about 600 mg, from about 400 mg to about 600 mg, or fromabout 200 mg to about 400 mg. In some embodiments of the methods, theamount of deferiprone in the composition (e.g., a tablet) is about 100mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600mg, about 800 mg, about 1000 mg, about 1100 mg, about 1200 mg, about1300 mg, about 1400 mg, about 1500 mg, or any range of values thereof.In particular, the amount of deferiprone in the composition (e.g., atablet) is 600 mg or 1000 mg deferiprone. In some embodiments, theamount of deferiprone in the tablet is 1000 mg deferiprone. In someembodiments, the amount of deferiprone in the tablet is 600 mgdeferiprone.

In some embodiments of the methods, the total daily dose of deferiproneis from about 100 mg/day to about 3000 mg/day, about 200 mg/day to about3000 mg/day, from about 400 mg/day to about 2400 mg/day, from about 600mg/day to about 2400 mg/day, from about 800 mg/day to about 2400 mg/day,from about 1200 mg/day to about 2400 mg/day, from about 1600 mg/day toabout 2400 mg/day, from about 1800 mg/day to about 2400 mg/day, fromabout 2000 mg/day to about 2400 mg/day, from about 400 mg/day to about2000 mg/day, from about 600 mg/day to about 2000 mg/day, from about 800mg/day to about 2000 mg/day, from about 1200 mg/day to about 2000mg/day, from about 1600 mg/day to about 2000 mg/day, from about 1800mg/day to about 2000 mg/day, from about 400 mg/day to about 1800 mg/day,from about 600 mg/day to about 1800 mg/day, from about 800 mg/day toabout 1800 mg/day, from about 1200 mg/day to about 1800 mg/day, fromabout 1600 mg/day to about 1800 mg/day, from about 400 mg/day to about1600 mg/day, from about 600 mg/day to about 1600 mg/day, from about 800mg/day to about 1600 mg/day, from about 1200 mg/day to about 1600mg/day, from about 400 mg/day to about 1200 mg/day, from about 600mg/day to about 1200 mg/day, from about 800 mg/day to about 1200 mg/day,from about 400 mg/day to about 800 mg/day, from about 600 mg/day toabout 800 mg/day, or from about 400 mg/day to about 600 mg/day. In someembodiments of the methods, the total daily dose of deferiprone is about200 mg/day, about 400 mg/day, about 600 mg/day, about 800 mg/day, about1000 mg/day, about 1200 mg/day, about 1400 mg/day, about 1600 mg/day,about 1800 mg/day, about 2000 mg/day, about 2200 mg/day, about 2400mg/day, about 2600 mg/day, about 2800 mg/day, about 3000 mg/day, or anyrange of values thereof.

In some embodiments of the methods, the composition (e.g., a tablet) isadministered once, twice, or three times a day. In some embodiments, thecomposition (e.g., a tablet) contains about 100 mg, about 200 mg, about400 mg, about 600 mg, about 800 mg, about 1000 mg, about 1200 mg, about1600 mg, about 1800 mg, about 2000 mg, about 2200 mg, or about 2400 mgof deferiprone and is administered once, twice, or three times a day. Insome embodiments, the composition (e.g., a tablet) contains about 600 mgof deferiprone and is administered once or twice a day.

In some embodiments, the composition (e.g., a tablet) contains about100, 200, 300, or 400 mg of deferiprone and is administered once, twice,or three times a day. In some embodiments, the composition (e.g., atablet) contains about 400 mg of deferiprone and is administered once,twice, or three times a day. In some embodiments, the composition (e.g.,a tablet) contains about 500 mg of deferiprone and is administered once,twice, or three times a day. In some embodiments, the composition (e.g.,a tablet) contains about 1000 mg of deferiprone and is administeredonce, twice, or three times a day.

Such embodiments disclosed herein can be used to avoid or reduce therisk of gastric distress and/or to treat iron overload in a subject(e.g., suffering from thalassemia, myelodysplasia, or sickle celldisease) or a neurodegenerative disease (e.g., amyotrophic lateralsclerosis).

VI. Methods of Making

In some embodiments, the pharmaceutical composition is prepared for oraldelivery. In some aspects, the disclosure is directed to making adelayed release deferiprone tablet disclosed herein.

In some embodiments, the method for making a delayed release deferipronetablet comprises (a) mixing deferiprone and one or more excipients; (b)compressing the mixture of (a) into a tablet core; and (c) coating thetablet core with an enteric coating suspension or solution. The methodcan further comprise (d) scoring the tablet core.

In some embodiments, the method for coating a core with an entericcoating solution or suspension comprises spray coating. In the case ofcoating by spray coating, the operation can be performed according togeneral coating methods, e.g., a tablet core is spray-coated with anenteric coating solution or suspension according to, for example, afluidized bed coating method, a pan coating method, or the like.

In some embodiments, the enteric coating solution or suspensioncomprises an enteric polymer. In some embodiments, the enteric polymeris about 1-50%, about 1-40%, about 5-40%, or about 5-30% of the entericcoating solution or suspension. In some embodiments, the enteric polymeris about 20-80%, about 25-75%, or about 30-70% of the enteric coatingwhen the coating has dried. In some embodiments, the enteric polymer isabout 50-60% by weight of the enteric coating when the coating hasdried. In some embodiments, the enteric polymer is about 55% by weightof the enteric coating when the coating has dried.

In some embodiments, the enteric coating suspension or solutioncomprises a plasticizer such as, e.g., diethyl phthalate, citrate esters(e.g., triethyl citrate), polyethylene glycol, glycerol, acetylatedglycerides, glycerin fatty acid ester, cetyl alcohol, stearyl alcohol,acetylated citrate esters, dibutylsebacate, castor oil, or combinationsthereof.

In some embodiments, the plasticizer is about 0.1-10%, about 0.1-5%,about 0.5-5%, or about 0.5-2% of the enteric coating suspension orsolution. In some embodiments, the plasticizer is about 1-10% or about4-8% by weight of the enteric coating when the coating has dried. Insome embodiments, the plasticizer is about 6% by weight of the entericcoating when the coating has dried.

In some embodiments, the enteric coating suspension or solutioncomprises a lubricant or anti-tack agent (e.g., talc).

In some embodiments, the lubricant or anti-tack agent is about 0.5-10%,about 0.5-8%, about 0.5-5%, or about 1-5% of the enteric coatingsuspension or solution. In some embodiments, the lubricant or anti-tackagent is about 10-30% or about 15-25% by weight of the enteric coatingwhen the coating has dried. In some embodiments, the lubricant oranti-tack agent is about 20% by weight of the enteric coating when thecoating has dried.

In some embodiments, the enteric coating suspension or solution canfurther comprise a diluent, e.g., a sugar (e.g., lactose, sucrose,fructose, mannitol and mixtures thereof).

In some embodiments, the diluent is about 0.5-10%, about 0.5-8%, about0.5-5%, or about 1-5% of the enteric coating suspension or solution. Insome embodiments, the diluent is about 10-30% or about 15-25% by weightof the enteric coating when the coating has dried. In some embodiments,the diluent is about 20% by weight of the enteric coating when thecoating has dried.

In some embodiments, the enteric coating can be applied as a solution ora latex suspension in organic solvents or aqueous solvents or mixturesthereof. Solvents such as water, lower alcohol, lower chlorinatedhydrocarbons, ketones, or mixtures thereof can be used.

In some embodiments, the solvent is about 20-80%, about 30-80%, about40-80%, or about 50-75% of the enteric coating solution or suspension.

In some embodiments, at least one ionic, nonionic or polymericsurfactant can be added as a stabilizing agent to the enteric coatingsuspension or solution. Suitable examples of the surfactant includediethanolamine, fatty acids, hydroxypropylmethylcellulose,hydroxypropylcellulose, monoethanolamine, nonoxynol, octoxynol, oleicacid, Poloxamers, polyoxyethylene 50 stearate, polyoxy fatty acids,polyoxyl hydrocarbon ethers, polysorbates (e.g., Polysorbate 80, etc.),povidone, fatty acid salts, sodium lauryl sulfate, sorbitan esters,trolamine and the like, but are not limited to these.

In some embodiments, the enteric coating solution or suspensioncomprises a plasticizer, a diluent, lubricant or anti-tack agent, and anenteric polymer.

After coating, in some embodiments, an antistatic agent such as talc canbe used as well.

By coating a tablet core disclosed herein with a coating layer using themethods disclosed herein, immediate dissolution of the physiologicallyactive substance from the enteric granule at acidic pH (e.g., pH 1 to4), which corresponds to dissolution in the vicinity of the stomachduring the early stage after oral administration, is suppressed, andsubsequent dissolution of the physiologically active substance at weaklyacidic to weakly alkaline pH (e.g., pH 4.5 to 8), which corresponds todissolution in the small intestine and thereafter, especially in theduodenum to ileum, is facilitated. In particular, it is possible to morestrictly control the dissolution during the early stage afteradministration.

VII. Methods of Use

The present disclosure provides methods of using the pharmaceuticalcompositions disclosed herein. In some embodiments, the pharmaceuticalcomposition is for oral delivery. Preferably, the pharmaceuticalcomposition is a tablet for oral delivery. In some embodiments, thepharmaceutical composition is a tablet (e.g., a delayed release tabletdisclosed herein).

For example, the most common adverse event with immediate releasetablets of deferiprone (Ferriprox®) is that it causes significantgastric distress. Such discomfort can cause patients to refrain fromtaking the medication, leading to a worsening of their condition. Inaddition, GI distress can impair health-related quality of life and leadto physical, mental, and social distress. Spiegel, Am J Gastroenterol.2011 March; 106(3):380-5, incorporated herein by reference in itsentirety. In some embodiments, the compositions, e.g., delayed releasetablets, of the present disclosure are formulated to reduce gastricdistress, a problem that occurs in about 15-30% of patients who begintherapy with deferiprone. In some embodiments, the compositions, e.g.,delayed release tablets, disclosed herein have negligible dissolution inthe stomach, so as to minimize the gastric distress and yet achievesufficient rapid dissolution in the intestines to enable the desiredrate of release in the intestines. In some embodiments, thecompositions, e.g., delayed release tablets, disclosed herein havenegligible dissolution in the stomach, so as to minimize the gastricdistress and yet achieve similar, but not identical serum concentrationtime profiles, in vivo, as immediate release tablets of deferiprone,with the addition of a lag time of about one hour.

Certain embodiments of the disclosure are directed to a method forreducing gastric distress in a human subject in need of deferipronetreatment comprising administering a tablet (e.g., a scored delayedrelease deferiprone tablet) disclosed herein (e.g., a whole tablet, ahalf tablet, or a combination thereof).

Certain embodiments of the disclosure are directed to a method fordelayed release of deferiprone in a human subject comprisingadministering a tablet disclosed herein (e.g., a whole tablet, a halftablet, or a combination thereof). Certain embodiments of the disclosureare directed to a method of treating a medical condition in a humansubject, e.g., where deferiprone is desired, comprising administering atablet (e.g., a scored delayed release deferiprone tablet) disclosedherein (e.g., a whole tablet, a half tablet, or a combination thereof).

The compositions, e.g., delayed release tablets, of the presentdisclosure can be particularly useful in patients requiring bloodtransfusions for survival, such as Hemoglobinopathies, includingThalassemia and Sickle Cell Disease, or patients who have a secondarydestruction of their red blood cell forming capability, such as thosewith Myelodysplasia.

Deferiprone immediate release tablets (Ferriprox®) are currently used tominimize the toxicity of high concentrations of iron in the body,tissues or cells. Thalassemia is a form of inherited autosomal recessiveblood disorder characterized by abnormal formation of hemoglobin. Theabnormal hemoglobin results in inadequate oxygen transport and anaccelerated rate of destruction of red blood cells. People withthalassemia make less hemoglobin and have fewer circulating red bloodcells than normal, which results in moderate to severe anemia. Patientsrequire life-long blood transfusions to treat their thalassemia,typically every 2-4 weeks, and each blood transfusion results in anincrease of iron into the body, equivalent to the amount that isnormally absorbed from food in the gut over 6 months. Since there is noexcretory pathway for iron, this excess will cause iron overload,particularly in the liver and other more sensitive tissues withresultant endocrine disorders and iron-induced cardiovascular illness.

Iron overload occurs in sickle cell disease (SCD) patients who requireregular chelation therapy. Voskaridou et al., Ann Hematol. 2005 July;84(7):434-40, incorporated herein by reference in its entirety. AlthoughSickle Cell Disease is a different hemoglobinopathy, patients withSickle Cell Disease who require blood transfusions to survive alsosuffer from iron-toxicity. This is also the case in patients withMyelodysplasia who require repeated blood transfusions.

In some embodiments, the medical condition treated by a composition,e.g., a delayed release tablet, of the present disclosure is ironoverload. In some aspects, the medical condition treated by acomposition, e.g., a delayed release tablet, is transfusional ironoverload in a subject whose prior chelation therapy is inadequate. Insome aspects, the medical condition treated by a composition, e.g., adelayed release tablet, is transfusional iron overload in a subject whohas a cardiac MRI T2* of 20 ms or less (e.g. 10 ms). In someembodiments, the medical condition treated by a composition, e.g., adelayed release tablet, of the present disclosure is in transfusedpatients with thalassemia. In some embodiments, a composition, e.g., adelayed release tablet, of the present disclosure is used for treatingtransfusional iron overload in patients with Sickle Cell Disease. Insome embodiments, a tablet (e.g., a scored delayed release deferipronetablet) of the present disclosure is used for treating transfusionaliron overload in patients with Myelodysplasia.

The compositions, e.g., delayed release tablets, of the presentdisclosure can also be particularly useful in patients withneurodegenerative disease such as Parkinson's disease, amyotrophiclateral sclerosis (ALS), or Huntington's disease because the tablets arenot dissolved in the stomach, thus in some instances minimizing thegastric distress, accompanied by nausea and vomiting, that is prominentin patients who start deferiprone. Equally important, the DR tablets ofthe present disclosure are less rapidly absorbed than IR tablets andother known deferiprone tablets, leading to less nausea and vomiting,where that may be contributing to the GI distress. Yet, the DR tabletsof the present disclosure are sufficiently rapidly absorbed afterreaching the duodenum, to enable ready penetration into the brain,thereby enabling deferiprone to exhibit its beneficial effects inParkinson's disease, ALS, Huntington's disease and otherneurodegenerative diseases where localized accumulation of ironcontributes to the pathology of the disease.

Parkinson's disease is a degenerative disorder of the central nervoussystem. The motor symptoms of Parkinson's disease result from the deathof dopamine-generating cells in the substantia nigra, a region of themidbrain. Early in the course of the disease, the most obvious symptomsare movement-related, e.g., shaking, rigidity, slowness of movement anddifficulty with walking and gait. Later in the course of the disease,thinking and behavioral problems can arise, with dementia commonlyoccurring in the advanced stages of the disease, and depression is themost common psychiatric symptom. Other symptoms include sensory, sleepand emotional problems. Parkinson's disease is more common in olderpeople, with most cases occurring after the age of 50.

The pathology of Parkinson's disease is characterized by theaccumulation of a protein called alpha-synuclein into inclusions calledLewy bodies in neurons, along with insufficient formation and activityof dopamine produced in certain neurons within parts of the midbrain.The anatomical distribution of the Lewy bodies is often directly relatedto the expression and degree of the clinical symptoms of eachindividual. Diagnosis of typical cases is mainly based on symptoms, withtests such as neuroimaging being used for confirmation.

Early motor symptoms of the disease are commonly managed through thetreatment with L-DOPA and dopamine agonists. As the disease progressesand dopaminergic neurons continue to be lost, these drugs eventuallybecome ineffective at treating the symptoms and at the same time producea complication called dyskinesia, marked by involuntary writhingmovements. Diet and exercise and some forms of rehabilitation have shownsome effectiveness in alleviating symptoms. Surgery and deep brainstimulation have been used to reduce motor symptoms as a last resort insevere cases where drugs are ineffective. There is no cure forParkinson's disease.

Huntington's disease is a progressive brain disorder cause by adefective gene (HTT) on chromosome 4 that codes for a protein calledhuntingtin. The defect causes expansion of CAG(cytosine-adenine-guanine) triplet repeats in the gene coding huntingtinwhich damages cells in the brain. A diagnostic genetic test for thedefective huntingtin gene is available.

Symptoms of Huntington's disease usually develop between ages 30 and 50and include uncontrolled movement of the arms, legs, head, face andupper body. Huntington's disease also causes a decline in thinking andreasoning skills, including memory, concentration, judgment and abilityto plan and organize. Huntington's disease brain changes lead toobsessive-compulsive thoughts and actions and alterations in mood, suchas depression, anxiety, anger and irritability.

There is no cure for Huntington's disease, and treatments focus onmanaging Huntington's disease symptoms. For example, antipsychotic drugssuch as olanzapine are used to treat chorea (involuntary movements),antipsychotic drugs or selective serotonin reuptake inhibitors are usedto treat irritability, and selective serotonin reuptake inhibitors areused to treat obsessive-compulsive thoughts or actions.

Amyotrophic lateral sclerosis (ALS) is a disease that causes death ofthe neurons which control voluntary muscles. ALS is also known as LouGehrig's disease or motor neurone disease (MND). ALS is characterized bystiff muscles, muscle twitching, and gradual weakening of the musclesdue decreased muscle size. This results in difficulty speaking,swallowing and eventually breathing. The cause is not known in 90-95% ofALS cases, while about 5-10% of ALS cases are genetically inherited. ALSdiagnosis is based on a person's signs and symptoms with testing done torule out other potential causes.

There is no cure for ALS. Non-invasive ventilation may improve qualityand length of life. Riluzole, a sodium channel blocking drug, can delaythe onset of ventilator dependence or tracheostomy and may increasesurvival by approximately 2-3 months. However, the average survival fromonset to death is typically 2-4 years.

In some embodiments, the medical condition treated by a composition,e.g., a tablet (e.g., a scored delayed release deferiprone tablet),disclosed herein is a neurodegenerative disease. In some embodiments,the neurodegenerative disease is Parkinson's disease, amyotrophiclateral sclerosis (ALS), Huntington's disease,Pantothenate-Kinase-associated neurodegeneration, or Friedreich'sAtaxia.

Accordingly, certain embodiments of the disclosure are directed tomethods for treating a neurodegenerative disease comprising acomposition described herein. In some embodiments, the neurodegenerativedisease is Parkinson's disease, amyotrophic lateral sclerosis (ALS),Huntington's disease, Friedreich's Ataxia, Pantothenate KinaseAssociated Neurodegeneration (PKAN), or neurodegeneration with brainiron accumulation (NBIA). Some embodiments are directed to methods ofreducing or slowing progression of a disability associated with ALS. Insome embodiments, the subject is further administered riluzole. In someembodiments, the deferiprone is administered prior to, after or at thesame time as the riluzole is administered to the subject. In someembodiments, the total daily dose of riluzole is about 20 mg/day toabout 500 mg/day.

In some embodiments, the composition is a tablet, a delayed releasetablet, a scored delayed release tablet, a whole tablet, a half tablet,or a combination thereof. In some embodiments, the composition isadministered by a dosing regimen described herein. In some embodiments,the composition is administered in a fasted state or a fed state.

Certain aspects of the disclosure are directed to a method for treatinga human subject with iron overload, comprising orally administering tothe subject in need thereof 3000 mg/day or 1200 mg/day deferiprone,wherein the subject is administered the deferiprone two times per day.In some embodiments, the subject suffers from thalassemia ormyelodysplasia. In some embodiments, the subject suffers from aneurogenic disease. In some embodiments, the 3000 mg/day deferiprone isadministered at a dose of 1500 mg two times a day (e.g., one and a half1000 mg DR tablets; or three half 1000 mg DR tablets). In someembodiments, the subject exhibits a C_(max) of 48.5-10.5 μg/mL at steadystate. In some embodiments, the subject exhibits an AUC₍₀₋₂₄₎ of 75-95μg·h/mL at steady state. In some embodiments, the 1200 mg/daydeferiprone is administered at a dose of 600 mg two times a day. In someembodiments, the 1200 mg/day deferiprone is administered at a dose of1200 mg one time per day. In some embodiments, the subject exhibits aC_(max) of 4.00 to 13.558 μg/mL after administration of 600 mgdeferiprone in the fed state. In some embodiments, the subject exhibitsa C_(max) of 5.880 to 13.690 μg/mL after 600 mg deferiprone in thefasted state. In some embodiments, the subject exhibits a T_(max) of1.333 to 8.000 hours after administration of 1200 mg deferiprone. Insome embodiments, the subject exhibits a AUC_(I)/C_(max) of 3.265 to6.765 hr after administration of 1200 mg deferiprone.

In some embodiments of these methods, the subject suffers fromParkinson's disease. In some embodiments of these methods, the subjectsuffers from Huntington's disease. In some embodiments of these methods,the subject suffers from amyotrophic lateral sclerosis (ALS).

VIII. Bioavailability

Pharmacokinetic (PK) parameters (e.g., C_(max), T_(max), AUCT, AUCI,K_(el), T_(1/2)) can be assessed for subjects administered a tabletdisclosed herein. In some embodiments, the PK parameters are determinedby a single dose study. In some embodiments, the PK parameters aredetermined in a multi-dose or steady state study.

In certain embodiments, a tablet disclosed herein, provides a meanAUC_(∞)/C_(max) ratio between 3.5 hours and 6.0 hours in single dosebioequivalence studies in both fasted and fed state when the tablet isadministered as a whole tablet and when administered as half tablet.

While the present application has been illustrated by the description ofembodiments thereof, and while the embodiments have been described indetail, it is not the intention of the applicants to restrict or in anyway limit the scope of the appended claims to such detail. Additionaladvantages and modifications will readily appear to those skilled in theart, having the benefit of the present application. Therefore, theapplication, in its broader aspects, is not limited to the specificdetails, illustrative examples shown, or any apparatus referred to.Departures may be made from such details, examples and apparatuseswithout departing from the spirit or scope of the general inventiveconcept.

EXAMPLES

The working of the invention might be better understood from thefollowing examples, which are intended to be illustrative and notlimiting of the scope of the invention.

Example 1: Preparation of Enteric Coated Delayed Release Tablets

TABLE 1 Deferiprone Delayed Release Tablet (1000 mg and 600 mg) AmountAmount (1000 mg) (600 mg) Component Function mg % mg % DeferiproneActive 1000 89.6 600 88.7 HPMCAS-LF Enteric 28 2.51 29.5 4.36 polymerMagnesium pH adjusting 50 4.48 24.5 3.62 oxide agent Colloidal SiliconGlidant 2.6 0.23 1 0.15 Dioxide (part 1) Subtotal 1080.6 96.8 655 96.8Post Compaction Magnesium Lubricant 17.2 1.54 4 0.59 stearate ColloidalSilicon Glidant 2.2 0.20 1 0.15 Dioxide (part 2) Total 1100 98.5 66097.6 Coating Triethyl Citrate Plasticizer 1.03 0.09 1.03 0.15 SucroseDiluent 3.09 0.28 3.09 0.46 Talc Anti-tacking 3.09 0.28 3.09 0.46 agent*Methacrylic Enteric 31 0.83^(#) 31 1.37^(#) Acid Copolymer polymerDispersion **Purified Water 124 — 126.8 — TOTAL 1116.5 100 676.5 100COATED TABLET *Contains 30% solids. **Evaporates during the coatingprocess. ^(#)The weight percentage of methacrylic acid copolymer in thecoating when the coating has dried.

To prepare the tablet core, deferiprone, HPMCAS, magnesium oxide, andcolloidal silicon dioxide (part 1) were mixed together, and the mixturewas compacted and milled into granules. Magnesium stearate and colloidalsilicon dioxide (part 2) were added to and mixed with the granules, andthe resulting mixture was compressed into core tablets of about 1100 mgor about 660 mg weight on capsule-shape tooling, bisected on both sides.

The enteric coating suspension was sprayed onto the deferiprone coretablets in a side-vented coating pan until the tablets had a targetedweight gain of approximately 1.5% for the 1000 mg tablets and 2.5% forthe 600 mg tablets. The resulting delayed release tablet was designed tohave negligible dissolution in the stomach, but rapidly dissolve in theduodenum, for preventing gastric distress. These properties apply to thewhole tablet and the half tablet.

Example 2: Dissolution Characteristics of Delayed Deferiprone Tablet(Whole and Half)

The dissolution characteristics of the 1000 mg delayed releasedeferiprone tablet prepared in Example 1 was tested in vitro using bothwhole and half tablets.

Dissolution testing was performed in USP apparatus 2, at 75 rpm, in 900mL of 0.1 N hydrochloric acid (HCl), 0.5 M phosphate buffer at pH 4.5,and 0.5 M phosphate buffer at pH 6.8. The 1000 mg tablets of Example 1showed the following dissolution characteristics for both whole tabletsand half tablets:

Dissolution was below 20% at 180 minutes in 0.1 N HCl [FIG. 1 ].

Dissolution was above 60% at 60 minutes in pH 6.8 [FIG. 2 ].

Dissolution was above 80% at 60 minutes in pH 4.5 [FIG. 3 ].

Example 3: Comparison of Dissolution Rates for Delayed Release vs.Enteric Coated Deferiprone Tablets

The dissolution profile for the whole and half delayed release 1000 mgtablet prepared in Example 1 were compared to the dissolution profilefor whole and half enteric coated (EC) tablets (Avicenna Lab, IranianPat. Appl. No. 90-07-27-71996).

The EC tablet (Avicenna Lab) used for comparison included a core tabletof 500 mg deferiprone, 290 mg microcrystalline cellulose, 1 mg colloidalsilicon dioxide, and 9 mg magnesium stearate (800 mg total core weight).The EC tablet (Avicenna Lab) also included a coating of 34.68 mgmethacrylic acid copolymer, 15.56 mg talc, 3.61 mg PEG 6000, 4.38 mgtitanium dioxide, 4.93 mg hypromellose, 6 cm Poaz, and 0.82 mg sodiumbicarbonate (63.98 mg total weight of coating). The weight of thecoating is about 7.4% of the total weight of the EC tablet.

Dissolution testing was carried out in a USP Apparatus II at 75 rpmusing 900 mL of 0.1N HCl for 180 minutes. Samples were collected at 5minute intervals to characterize the dissolution profile of the tablets.

In sum, the whole and half delayed release deferiprone tablets fromExample 1 had dissolution below 20% at 60, 90, 120, 150, and 180 minutesin 0.1 N HCl (representing the pH of the stomach). No dissolution in 0.1N HCl was observed for the whole EC tablet (Avicenna Lab), but rapid andcomplete dissolution were observed in buffered solutions: 95% dissolvedat 30 min in a pH 4.5 solution; 94% dissolved at 30 min in a pH 6.0solution; and 88% dissolved at 30 min in a pH 6.8 solution. However, thehalf EC tablets (Avicenna Lab) rapidly dissolve, thus losing theirenteric coating properties.

Thus, the delayed release formulation of Example 1 demonstrated anadvantage over other enteric-coated tablets of deferiprone. Inparticular, the 1000 mg delayed release tablet of Example 1 exhibits adelayed release in a milieu, representing the pH of stomach acid, buthas attributes beyond that provided by an enteric coating. Specifically,the new delayed release tablet of the invention confers a similar rateof dissolution with half and whole tablets, independent of the pH of thedissolving media. That is, the delayed release tablet embraces certainattributes of an enteric coated tablet, without its deficiencies, sothat tablets can be halved to enable fine tuning of the dosing toadminister half tablets.

Examples 4-5: 24 Hour Bioequivalence Studies

Examples 4-5 relate to bioequivalence studies in human subjects, usingthe 1000 mg delayed release tablet of deferiprone in Example 1 andFerriprox® IR tablets.

The first study (Example 4) was a single dose study, which showed adelay in the absorption of the DR tablets, but not an increase in theterminal half-life, and also that half tablets had a similar rate andextent of absorption as whole tablets, whether or not they wereadministered with food.

The second study (Example 5) was a multiple dose study of equivalentdaily doses of DR and IR tablets. This study showed that at steadystate, the DR tablets were bioequivalent in the steady state to the IRtablets.

Example 4: Single Dose Pharmacokinetic Study of Deferiprone DelayedRelease Tablets Under Fasting and Fed Conditions Versus Ferriprox®Immediate Release Tablets Under Fed Conditions in Healthy Volunteers

This was a randomized, single dose, open-label, 4-period, 4-sequencecrossover study in healthy male and female volunteers. Subjects wererandomized to receive single doses of the following treatments indifferent sequences, with a 7-day washout period between drugadministrations:

One intact 1000 mg tablet of deferiprone DR under fasting conditions(n=23);

One intact 1000 mg tablet of deferiprone DR under fed conditions (n=21);

Two half-tablets (total 1000 mg) of deferiprone DR under fed conditions(n=26); and

Two 500 mg tablets of Ferriprox® IR formulation under fed conditions(n=24).

The objectives of the study were to evaluate the effect of food on thePK profile of a single dose of deferiprone DR, to compare the PK profileof the half-tablets to that of the intact tablet, to compare the PKprofile of deferiprone DR to that of Ferriprox® IR, and to evaluate thesafety and tolerability of a single dose of deferiprone DR.

The main PK parameters of this study are shown in Table 2, and therelative bioavailability is shown in Table 3. Under fed conditions, thetime (T_(max)) to reach the maximum serum concentration (C_(max)) ofdeferiprone was longer with the DR formulation (3.00 hours) comparedwith the IR formulation (1.33 hours). The C_(max) for the DR formulationwas about 65% of that for the IR formulation. Post-absorption serum druglevels declined at similar rates, with a half-life of approximately 1.8hours for both formulations. Moreover, there was no significantdifference in extent of exposure (AUC) to the drug between the twoformulations.

When the DR tablet was administered as half tablets, neither C_(max) norAUC differed significantly from whole tablet values. With respect to theeffect of food, the bioavailability of the DR formulation was the samewhether it was administered under fasting or fed conditions. Since thesame total dose was given for the DR and IR tablets, it was expectedthat the C_(max) would be higher for the IR tablets. However, theseresults provided evidence that 50% more deferiprone in a DR tablet couldbe given to achieve the same C_(max) as the IR tablet.

For each subject of the pharmacokinetic study, the ratio of AUC_(0-inf)over C_(max) was calculated (Table 4). The resulting ratio wastransformed by determining the natural logarithm of the ratio. The meanof the logarithmically transformed ratios across the subjects in thestudy was calculated and the mean log value was subsequently inverselytransformed to the normal scale by determining the anti-logarithm of themean value.

TABLE 2 Summary of Pharmacokinetic Parameters Deferiprone DR,Deferiprone DR, Deferiprone DR Deferiprone IR, Parameter (units) fastingfed half-tablets, fed fed C_(max) (μg/mL) Mean 6.133 (2.670-13.232)6.089 (2.908-9.514) 6.620 (3.236-12.419) 9.621 (3.731-19.125) (range)Standard Deviation 2.246 1.954 2.326 3.860 (SD) T_(max) (hours) Mean2.286 3.673 3.273 1.886 Median (range) 2.33 (1.33-4.00) 3.00 (2.00-8.00)2.67 (1.33-6.03) 1.33 (0.50-8.00) AUCT (μg · h/mL) 27.48 (29.2) 27.63(25.6) 28.52 (25.9) 29.64 (27.4) AUCI (μg · h/mL) 27.86 (29.2) 28.41(25.6) 29.05 (26.2) 30.26 (27.6) T_(half) (hours) 1.83 (11.7) 1.80(16.5) 1.77 (13.7) 1.79 (14.8)

TABLE 3 Relative Bioavailability of Deferiprone Delayed-Release TabletsRatio (90% CI) Deferiprone DR Deferiprone DR Fed Deferiprone DR vs.Parameter (units) Fed vs. Fasted whole vs. half IR, Fed C_(max) (μg/mL)98.7 (86.6-112.4) 89.0 (78.5-100.9) 65.5 (57.6-74.5) AUCT (μg · h/mL)99.0 (95.2-102.9) 96.7 (93.2-100.4) 92.4 (88.9-96.0) AUCI (μg · h/mL)100.0 (96.3-103.8)  97.5 (94.1-101.1) 93.1 (89.7-96.7)

TABLE 4 AUCI/Cmax DR 1000 mg DR 1000 mg DR 1000 mg IR 500 mg Ratiotablet - fasting tablet - fed half tablet - fed tablet - fed AUCI/Cmax(hr) 4.735 (2.858-6.596) 4.763 (3.225-8.506) 4.423 (3.174-6.529) 3.225(2.073-4.497) (range)

Example 5: Steady State Comparative Bioavailability of Study ofDeferiprone Delayed Release (DR) Tablets vs. Immediate Release (IR)Tablets at Steady State in Healthy Volunteers

A 2-period crossover study was conducted to assess the comparativebioavailability of 1000 mg deferiprone DR tablets (as shown inExample 1) and deferiprone (Ferriprox®) IR tablets at steady state in 35healthy volunteers. Subjects were randomized to receive the followingtwo treatments, separated by 5 days of washout:

Treatment A: Deferiprone DR, 1500 mg (one and a half 1000 mg tablets)every 12 hours (BID) (total of 3000 mg/day) for 3 days, administeredunder fed conditions; and

Treatment B: Ferriprox® IR, 1000 mg (two 500 mg tablets) every 8 hours(TID) (total of 3000 mg/day) for 3 days, administered under fedconditions.

After appropriate screening and baseline testing, subjects wereadministered deferiprone BID or TID, as applicable, on Days 1-3.Following a washout period, they returned to the site in the evening ofDay 8 and received the other treatment over Days 9-11 and checked out inthe morning of Day 12.

For each period, blood samples for pharmacokinetic (PK) assessment weretaken prior to the first dose of the day on the first two days of dosing(Days 1-2 and Days 9-10), and then at specified time points post-doseover a 24-hour period on the third day (Day 3 and Day 11).

The PK comparisons between deferiprone DR and Ferriprox® IR were done atsteady state (i.e., using the data for the 0-24 hour interval on thethird day for each treatment).

Statistical analysis for of AUC_(0-24hr-ss), C_(max-ss), C_(min-ss),C_(24-ss), T_(max-ss), are based on an ANOVA model. The two-sided 90%confidence interval of the difference between treatments were calculatedfor each parameter. The data of AUC_(0-24hr-ss), C_(max-ss), C_(min-ss),and C_(24-ss) were log-transformed prior to the ANOVA.

Criteria for bioequivalence in the steady state were established by the90% confidence interval for AUC_(0-24hr-ss) and C_(max-ss) that neededto be within 80-125%.

Summaries of the study results for DR Deferiprone tablets BID and IRtablets TID in subjects at steady state are shown in Tables 5 and 6, andFIG. 4 .

TABLE 5 PK Results for Deferiprone DR Tablets BID and IR Tablets TID inSubjects at Steady State Treatment A Treatment B (Deferiprone DR) ^(a)(Deferiprone IR) ^(b) (n = 35) (n = 35) Parameter (units) Mean (C.V. %)Mean (C.V. %) C_(max, ss) (μg/mL) 9.587 (21.1) 10.798 (27.9) T_(max, ss)(hours)^(c) 3.67 (1.50-17.00) 9.00 (0.50-18.00) AUC_((0-24)ss) (μg ·h/mL) 83.634 (22.4) 83.364 (23.3) ^(a) One and a half 1000 mg tabletsb.i.d. (every 12 hours) for a total of 3000 mg/day, for 3 consecutivedays. ^(b) Two 500 mg tablets t.i.d. (every 8 hours), for a total of3000 mg/day, for 3 consecutive days. ^(c)Median (range) is presented.T_(max) was calculated from the 1st dose of the day.

TABLE 6 Comparison of Results for Steady State Bioequivalence ofDeferiprone DR Tablets BID and IR Tablets TID 90% Confidence Limits (%)Parameter (units) Ratio Lower Upper C_(max, ss) (μg/mL) 88.74 83.0094.89 AUC_((0-24 h)ss) (μg · h/mL) 99.31 97.03 101.63

The results demonstrate that over a 24 hour period, the DR tablets, whengiven twice a day, were able to achieve the same maximum peakconcentrations (C_(max)) as the IR tablets, when given three times aday, and that the total amount absorbed (AUC) was essentially the samefor both products over a 24 hour period when the total daily dose wasthe same.

Example 6: Bioavailability of Deferiprone Delayed Release (DR) 600 mgTablets vs. Oral Solution in Healthy Volunteers

In this study, healthy subjects were randomized to receive the followingfour treatments in different orders, with a 7-day washout period betweentreatments:

Treatment A: Deferiprone DR, 1200 mg (two 600 mg tablets) single doseunder fed conditions (n=18);

Treatment B: Deferiprone DR, 1200 mg (two 600 mg tablets) single doseunder fasting conditions (n=17);

Treatment C: Deferiprone DR, 1200 mg (four half-tablets) single doseunder fed conditions (n=18); and

Treatment D: Oral solution (Ferriprox®, 1200 mg (100 mg/mL) single doseunder fasting conditions (n=17).

Blood samples were collected pre-dose and over a 24-hour intervalpost-dose. PK parameters (C_(max) and T_(max)) are shown in Table 7. Theratio of AUCI to C_(max) is shown in Table 8. These results show thatthe C_(max) for the 600 mg DR tablets is about half of the C_(max) ofthe oral solution, and the AUCI/C_(max) for the 600 mg DR tablet isabout twice the ratio for the oral solution.

TABLE 7 Cmax (μg/mL) and Tmax (hr) Treatment A Treatment B Treatment CTreatment D (DR 600 mg (DR 600 mg (DR 600 mg half (Oral solution -Parameter (units) tablets - fed) tablets - fasted) tablets - fed)fasted) C_(max) (μg/mL) Mean 8.047 (4.300-13.558) 8.214 (5.880-13.690)7.429 (4.551-12.321) 16.712 (8.613-24.059) (Range) SD 2.845 2.181 2.0044.540 T_(max) (hr) Mean 3.926 (1.333-8.000; 2.051 (1.333- 3.500; 3.494(1.333-8.000; 0.522 (0.250-1.000; (Range; median) 4.000) 2.000) 3.108)0.500)

TABLE 8 AUCI/C_(max) Treatment A Treatment B Treatment C Treatment D (DR600 mg (DR 600 mg (DR 600 mg half (Oral solution - Ratio tablets - fed)tablets - fasted) tablets - fed) fasted) AUCI/C_(max) (hr) Mean 4.758(3.265-6.765) 4.393 (3.511- 5.884) 5.004 (3.567-7.589) 2.490(1.633-3.277) (Range)

Example 7: Preparation of Enteric Coated Delayed Release Tablets

TABLE 9 600 mg Deferiprone Delayed Release Tablets Amount (600 mg)Component Function mg % Deferiprone Active 600 87.7 Hypromellose AcetateRelease controlling 29.5 4.31 Succinate(NF) AS-LF polymer Magnesiumoxide pH adjusting agent 24.5 3.58 Colloidal Silicon Dioxide Glidant 10.1462 (part 1) Subtotal 655 95.7 Post Compaction Magnesium stearateLubricant 4 0.585 Colloidal Silicon Dioxide Glidant 1 0.1462 (part 2)Total 660 96.5 Coating Triethyl Citrate NF Plasticizer 1.032 0.1509Sucrose NF (extra fine) Coating agent 3.09 0.452 Talc USP 500 meshAnti-tacking agent 2.09 0.306 *Methacrylic Acid Release controlling30.96 4.53 Copolymer Dispersion polymer NF Titanium Dioxide USPOpacifying agent 8.5 1.243 **Purified Water 154.3 22.6 TOTAL COATED 684100 TABLET *Contains 30% solids. **Evaporates during the coatingprocess.

To prepare the tablet core, deferiprone, hypromellose acetatesuccinate(NF) AS-LF, magnesium oxide light USP/EP, and colloidal silicondioxide (part 1) were mixed together, and the mixture was compacted andmilled into granules. Magnesium stearate and colloidal silicon dioxide(part 2) were added to and blended with the granules. The resultingmixture was compressed into core tablets. The tablets were then coated.

In addition to the various embodiments described herein, the presentdisclosure includes the following embodiments numbered E1 through E132.This list of embodiments is presented as an exemplary list and theapplication is not limited to these embodiments.

E1. A delayed release tablet comprising deferiprone for oraladministration to a human subject, wherein twice daily administration ofthe delayed release tablet is bioequivalent in the steady state to thesame daily dose of an immediate release tablet comprising deferiproneadministered three times daily.

E2. The tablet according to E1, wherein the tablet is a whole tabletthat is scored to facilitate breakage into half tablets.

E3. The tablet according to E2, wherein the half tablets arebioequivalent to the whole tablet in either the fasted state or the fedstate.

E4. The tablet according to E3, wherein half tablets are bioequivalentto the whole tablet in both the fasted state and the fed state.

E5. The tablet according to any one of E1 to E4, wherein the tabletconsists of: (a) a core comprising deferiprone in a therapeuticallyeffective amount and (b) an enteric coating.

E6. The tablet according to E5, wherein the core further comprises anenteric polymer.

E7. The tablet according to E6, wherein the enteric polymer in the coreis selected from the group consisting of hydroxypropyl methylcellulose(HPMC) acetate succinate, HPMC phthalate, polyvinyl acetate phthalate,methacrylic acid copolymers, a derivative thereof, and a combinationthereof.

E8. The tablet according to E7, wherein the enteric polymer is presentin an amount of about 1% to about 20% by weight of the core.

E9. The tablet according to any one of E1 to E8, wherein a single doseof the tablet provides a mean AUC_(∞)/C_(max) ratio between 3.5 hoursand 6.0 hours in fasted state when the tablet is administered to humansubjects.

E10. The tablet according to any one of E1 to E8, wherein a single doseof the tablet provides a mean AUC_(∞)/C_(max) ratio between 3.5 hoursand 6.0 hours in fed state when the tablet is administered to humansubjects.

E11. The tablet according to E9 or E10, wherein the tablet comprises1000 mg deferiprone.

E12. The tablet according to E9 or E10, wherein the tablet comprises 600mg deferiprone.

E13. The tablet according to E11, wherein the mean C_(max) is between2.670 and 13.232 μg/mL when the tablet is administered to humansubjects.

E14. The tablet according to E11, wherein the median T_(max) is between1.33 and 4.00 hours when the tablet is administered to human subjects.

E15. The tablet according to E11, wherein the median T_(max) is between2.00 and 8.00 hours when the tablet is administered to human subjects.

E16. The tablet according to E11, wherein the median T_(max) is between1.33 and 6.03 hours when the tablet is administered to human subjects.

E17. The tablet according to E11, wherein the ratio of AUCI/C_(max) isbetween 2.858 to 6.596 hours when the tablet is administered to humansubjects.

E18. The tablet according to E11, wherein the ratio of AUCI/C_(max) isbetween 3.225 to 8.506 hours when the tablet is administered to humansubjects.

E19. A tablet for oral administration of an active pharmaceuticalingredient to a human subject, wherein the tablet comprises: (a) a corecomprising the active pharmaceutical ingredient in a therapeuticallyeffective amount and an enteric polymer, and (b) an enteric coating,wherein the tablet is scored such that it can be administered as a wholetablet or a half tablet and wherein if the tablet is administered as oneor more half tablets, the half tablets are bioequivalent to the wholetablets in either the fasted state or the fed state.

E20. The tablet of E19, wherein the enteric polymer in the core isselected from the group consisting of hydroxypropyl methylcelluloseacetate succinate (HPMCAS), HPMC phthalate, polyvinyl acetate phthalate,methacrylic acid copolymers, a derivative thereof, and a combinationthereof.

E21. The tablet of E20, wherein the enteric polymer is present in anamount of about 1% to about 20% by weight of the core.

E22. The tablet according to any one of E19 to E21, wherein the activepharmaceutical ingredient is deferiprone.

E23. The tablet according to any one of E19 to E22, wherein twice dailyadministration of the tablet is bioequivalent in the steady state to thesame daily dose of the immediate release (Ferriprox®) tablet comprisingdeferiprone administered three times daily.

E24. The tablet according to any one of E19 to E23, wherein a singledose of the tablet provides a mean AUC_(∞)/C_(max) ratio between 3.5hours and 6.0 hours in fasted state when the tablet is administered tohuman subjects.

E25. The tablet according to any one of E19 to E23, wherein a singledose of the tablet provides a mean AUC_(∞)/C_(max) ratio between 3.5hours and 6.0 hours in fed state when the tablet is administered tohuman subjects.

E26. The tablet according to E24 or E25, wherein the tablet comprises1000 mg deferiprone.

E27. The tablet according to E24 or E25, wherein the tablet comprises600 mg deferiprone.

E28. The tablet according to E26, wherein the mean C_(max) is between2.670 and 13.232 μg/mL when the tablet is administered to humansubjects.

E29. The tablet according to E26, wherein the median T_(max) is between1.33 and 4.00 hours when the tablet is administered to human subjects.

E30. The tablet according to E26, wherein the median T_(max) is between2.00 and 8.00 hours when the tablet is administered to human subjects.

E31. The tablet according to E26, wherein the median T_(max) is between1.33 and 6.03 hours when the tablet is administered to human subjects.

E32. The tablet according to E26, wherein the ratio of AUCI/C_(max) isbetween 2.858 to 6.596 hours when the tablet is administered to humansubjects.

E33. The tablet according to E26, wherein the ratio of AUCI/C_(max) isbetween 3.225 to 8.506 hours when the tablet is administered to humansubjects.

E34. A tablet for oral administration of an active pharmaceuticalingredient comprising: (a) a core comprising the active pharmaceuticalingredient in a therapeutically effective amount and an enteric polymer,and (b) an enteric coating, the tablet being a whole tablet which isscored to facilitate breakage of the tablet into half tablets, whereinboth the whole and the half tablets display a delayed releasedissolution profile.

E35. The tablet according to E34, wherein the half tablets arebioequivalent to the whole tablets in either the fasted state or the fedstate.

E36. The tablet according to E35, wherein the enteric polymer in thecore is selected from the group consisting of hydroxypropylmethylcellulose acetate succinate (HPMCAS), HPMC phthalate, polyvinylacetate phthalate, methacrylic acid copolymers, a derivative thereof,and a combination thereof.

E37. The tablet according to E36, wherein the enteric polymer is presentin an amount of about 1% to about 20% by weight of the core.

E38. The tablet according to any one of E34 to E37, wherein the activepharmaceutical ingredient is deferiprone.

E39. The tablet according to any one of E34 to E38 wherein both thewhole and the half tablets exhibit dissolution below 20% at 60 minutesin 0.1 N HCl.

E40. The tablet according to any one of E34 to E39, wherein a singledose of the tablet provides a mean AUC_(∞)/C_(max) ratio between 3.5hours and 6.0 hours in fasted state when the tablet is administered tohuman subjects.

E41. The tablet according to any one of E34 to E39, wherein a singledose of the tablet provides a mean AUC_(∞)/C_(max) ratio between 3.5hours and 6.0 hours in fed state when the tablet is administered tohuman subjects.

E42. The tablet according to E40 or E41, wherein the tablet comprises1000 mg deferiprone.

E43 The tablet according to E40 or E41, wherein the tablet comprises 600mg deferiprone.

E44. The tablet according to E42, wherein the mean C_(max) is between2.670 and 13.232 μg/mL when the tablet is administered to humansubjects.

E45. The tablet according to E42, wherein the median T_(max) is between1.33 and 4.00 hours when the tablet is administered to human subjects.

E46. The tablet according to E42, wherein the median T_(max) is between2.00 and 8.00 hours when the tablet is administered to human subjects.

E47. The tablet according to E42, wherein the median T_(max) is between1.33 and 6.03 hours when the tablet is administered to human subjects.

E48. The tablet according to E42, wherein the ratio of AUCI/C_(max) isbetween 2.858 to 6.596 hours when the tablet is administered to humansubjects.

E49. The tablet according to E42, wherein the ratio of AUCI/C_(max) isbetween 3.225 to 8.506 hours when the tablet is administered to humansubjects.

E50. A tablet for oral administration comprising: (a) a core comprisingdeferiprone in a therapeutically effective amount and an entericpolymer; and (b) an enteric coating comprising an enteric polymer,wherein the tablet is suitable for twice daily dosing.

E51. The tablet of E50 which is scored to facilitate breakage of thetablet into half tablets.

E52. The tablet of E51 which can be administered as one or more wholetablets, one or more half tablets, or a combination thereof.

E53. The tablet according to any one of E50 to E52, wherein the entericpolymer in the core is selected from the group consisting ofhydroxypropyl methylcellulose acetate succinate (HPMCAS), HPMCphthalate, polyvinyl acetate phthalate, methacrylic acid copolymers, aderivative thereof, and a combination thereof.

E54. The tablet according to E53, wherein the enteric polymer is presentin an amount of about 1% to about 20% by weight of the core.

E55. The tablet according to any one of E50 to E54, wherein the entericpolymer in the enteric coating is selected from the group consisting ofhydroxypropyl methylcellulose acetate succinate (HPMCAS), HPMCphthalate, polyvinyl acetate phthalate, methacrylic acid copolymers, aderivative thereof, and a combination thereof.

E56. The tablet according to any one of E50 to E55, wherein the corefurther comprises a basic excipient and a glidant.

E57. The tablet according to E56, wherein the basic excipient isselected from the group consisting meglumine, metal oxides, metalhydroxides, basic salts of weak acids, and a combination thereof.

E58. The tablet according to E56 or E57, wherein the glidant iscolloidal silicon dioxide.

E59. The tablet according to any one of E56 to E58 further comprising alubricant.

E60. The tablet according to E59, wherein the lubricant is selected fromthe group consisting of magnesium stearate, calcium stearate, stearicacid, sodium stearyl fumarate, talc, and a combination thereof.

E61. The tablet according to any one of E54 to E60, wherein the entericcoating further comprises a plasticizer and an anti-tacking agent.

E62. The tablet according to E61, wherein the plasticizer is selectedfrom the group consisting of a citrate ester, diethyl phthalate,polyethylene glycol, glycerol, acetylated glycerides, acetylated citrateesters, dibutyl sebecate, castor oil, and a combination thereof.

E63. The tablet according to E61 or E62, wherein the tablet furthercomprises a diluent selected from the group consisting of sucrose,lactose, fructose, mannitol, and a combination thereof.

E64. The tablet according to E61 or E62, wherein the anti-tacking agentis talc.

E65. The tablet according to any one of E50 to E64, wherein a singledose of the tablet provides a mean AUC_(∞)/C_(max) ratio between 3.5hours and 6.0 hours in fasted state when the tablet is administered tohuman subject.

E66. The tablet according to any one of E50 to E64, wherein a singledose of the tablet provides a mean AUC_(∞)/C_(max) ratio between 3.5hours and 6.0 hours in fed state when the tablet is administered tohuman subjects.

E67. The tablet according to E65 or E66, wherein the tablet comprises1000 mg deferiprone.

E68. The tablet according to E65 or 66, wherein the tablet comprises 600mg deferiprone.

E69. The tablet according to E67, wherein the mean C_(max) is between2.670 and 13.232 μg/mL when the tablet is administered to humansubjects.

E70. The tablet according to E67, wherein the median T_(max) is between1.33 and 4.00 hours when the tablet is administered to human subjects.

E71. The tablet according to E67, wherein the median T_(max) is between2.00 and 8.00 hours when the tablet is administered to human subjects.

E72. The tablet according to E67, wherein the median T_(max) is between1.33 and 6.03 hours when the tablet is administered to human subjects.

E73. The tablet according to E67, wherein the ratio of AUCI/C_(max) isbetween 2.858 to 6.596 hours when the tablet is administered to humansubjects.

E74. The tablet according to E67, wherein the ratio of AUCI/C_(max) isbetween 3.225 to 8.506 hours. when the tablet is administered to humansubjects.

E75. A tablet comprising deferiprone for twice daily oraladministration, wherein a single dose administration of the tabletprovides a mean AUC_(∞)/C_(max) ratio between 3.5 hours and 6.0 hours inboth fasted and fed state when the tablet is administered as a wholetablet and when administered to human subjects as a half tablet.

E76. The tablet according to E75, wherein the mean AUC_(∞)/C_(max) ratiois about 4.0 hours to about 5.5 hours.

E77. The tablet according to E75 or E76, where the active pharmaceuticalingredient or the deferiprone is in an amount of about 100 mg to about1500 mg per tablet.

E78. The tablet according to any one of E75 to E77, wherein the totaldaily dose of the active pharmaceutical ingredient or the deferiprone isabout 100 mg/day, about 200 mg/day, about 300 mg/day, about 400 mg/day,about 500 mg/day, about 600 mg/day, about 700 mg/day, about 800 mg/day,about 900 mg/day, about 1000 mg/day, about 1200 mg/day, about 1500mg/day, about 1800 mg/day, about 2000 mg/day, about 2100 mg/day, about2400 mg/day, about 2500 mg/day, about 2700 mg/day, about 3000 mg/day,about 3300 mg/day, about 3500 mg/day, about 4000 mg/day, about 4500mg/day, about 5000 mg/day, about 5500 mg/day, about 6000 mg/day, about6500 mg/day, about 7000 mg/day, about 7500 mg/day, about 8000 mg/day,about 8500 mg/day, about 9000 mg/day, about 9500 mg/day, or about 10,000mg/day.

E79. The tablet according to any of E74 to E78, where the activepharmaceutical ingredient or the deferiprone is in an amount of about100 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, orabout 1500 mg per tablet.

E80. The tablet according to E79 which comprises a core comprising about1000 mg or about 600 mg of deferiprone, about 20 mg to about 80 mg of anenteric polymer, and about 5 mg to about 100 mg of a basic excipient.

E81. The tablet according to E80, further comprising a lubricant in anamount of about 7 mg to about 20 mg.

E82. The tablet according to E80 or E81 which comprises an entericcoating comprising about 7 mg to about 20 mg of an enteric polymer, andabout 0.5 mg to about 5 mg of a plasticizer.

E83. The tablet according to E79 which comprises a core comprising about600 mg deferiprone, about 20 mg to about 80 mg of an enteric polymer,and about 5 mg to about 100 mg of a basic excipient.

E84. The tablet according to E83, further comprising a lubricant in anamount of about 2 mg to about 10 mg.

E85. The tablet according to E83 or E84 which comprises an entericcoating comprises about 5 mg to about 20 mg of an enteric polymer, andabout 0.5 mg to about 5 mg of a plasticizer.

E86. The tablet according to any one of E75 to E85, wherein the tabletcomprises 1000 mg deferiprone.

E87. The tablet according to any one of E75 to E85, wherein the tabletcomprises 600 mg deferiprone.

E88. The tablet according to E86, wherein the mean C_(max) is between2.670 and 13.232 μg/mL when the tablet is administered to humansubjects.

E89. The tablet according to E86, wherein the median T_(max) is between1.33 and 4.00 hours when the tablet is administered to human subjects.

E90. The tablet according to E86, wherein the median T_(max) is between2.00 and 8.00 hours when the tablet is administered to human subjects.

E91. The tablet according to E86, wherein the median T_(max) is between1.33 and 6.03 hours when the tablet is administered to human subjects.

E92. The tablet according to E86, wherein the ratio of AUCI/C_(max) isbetween 2.858 to 6.596 hours when the tablet is administered to humansubjects.

E93. The tablet according to E86, wherein the ratio of AUCI/C_(max) isbetween 3.225 to 8.506 hours when the tablet is administered to humansubjects.

E94. The tablet according to any one of E1 to E93 which is scored tofacilitate breakage of the tablet into half tablets and can beadministered to a human subject as one or more whole tablets, one ormore half tablets, or any combination thereof.

E95. The tablet according to any one of E1 to E94, wherein the tabletreleases less than about 80% of the deferiprone within 60 minutes whenmeasured by USP Apparatus Type II Paddle Method at 75 rpm in 900 mLwater at 37±0.5° C.

E96. The tablet according to E95, wherein approximately 100% of thedeferiprone is released within about 90 minutes when measured by USPApparatus Type II Paddle Method at 75 rpm in 900 mL at pH 6.8 or 4.5.

E97. The tablet according to E96, wherein approximately 50% of thedeferiprone is released within about 30 minutes when measured by USPApparatus Type II Paddle Method at 75 rpm in 900 mL at pH 6.8 or 4.5.

E98. A method for treating a subject with iron overload, comprisingorally administering to the subject in need thereof the tablet of anyone of E1 to E97.

E99. The method according to E98, wherein the subject suffers fromthalassemia or myelodysplasia.

E100. The method according to E98, wherein the subject suffers fromtransfusional iron overload and whose prior chelation therapy isinadequate.

E101. The method according to E98, wherein the subject suffers fromtransfusional iron overload and has a cardiac MM T2* of 20 ms or less.

E102. A method for treating a subject with a neurodegenerative disease,comprising orally administering to the subject in need thereof thetablet of any one of E1 to E97.

E103. The method of E102, wherein the subject suffers from Parkinson'sdisease, amyotrophic lateral sclerosis (ALS), Huntington's disease,Friedreich's Ataxia, Pantothenate Kinase Associated Neurodegeneration(PKAN), or neurodegeneration with brain iron accumulation (NBIA).

E104. The method according to any one of E98 to E103, comprising aregimen of once daily or twice daily dosing (BID).

E105. The method according to any one of E98 to E104, wherein the tabletis administered to the subject as one or more whole tablets, one or morehalf tablets, or a combination thereof.

E106. The method according to any one of E98 to E105, wherein the tabletis administered to the subject in a fasted state or a fed state.

E107. The method according to any one of E98 to E106, wherein thedeferiprone is in an amount of about 100 mg to about 800 mg per tablet.

E108. The method according to any one of E98 to E107, wherein thedeferiprone is in an amount of about 400 mg per tablet.

E109. The method according to any one of E98 to E108, wherein the totaldaily dose of deferiprone is about 200 mg/day to about 2400 mg/day.

E110. The method according to any one of E98 to E109, wherein the totaldaily dose of deferiprone is about 400 mg/day to about 1200 mg/day.

E111. The method according to any one of E98 to E110, wherein the tabletis administered once or twice a day.

E112. The method according to any one of E98 to E111, wherein one, twoor three tablets are administered once or twice a day.

E113. The method according to any one of E98 to E112, wherein one, twoor three tablets are administered once, twice, or three times a day.

E113. The method according to any one of E103 to E112, wherein thesubject suffers from amyotrophic lateral sclerosis (ALS).

E114. The method according to any one of E103 to E113, wherein thetreatment reduces or slows progression of a disability associated withALS in the subject.

E115. The method according to E113 or E114, further comprisingadministering riluzole to the subject.

E116. A method for treating a human subject with iron overload,comprising orally administering to the subject in need thereof 3000mg/day deferiprone, wherein the subject is administered the deferipronetwo times per day.

E117. The method according to E116, wherein the subject suffers fromthalassemia or myelodysplasia.

E118. The method according to E116 or E117, wherein the 3000 mg/daydeferiprone is administered at a dose of 1500 mg two times a day.

E119. The method according to any one of E116 to E118, wherein thesubject exhibits a C_(max) of 48.5-10.5 μg/mL at steady state.

E120. The method according to any one of E116 to E119, wherein thesubject exhibits an AUC₍₀₋₂₄₎ of 75-95 μg·h/mL at steady state.

E121. The method according to any one of E98 to E120, wherein thesubject is administered a tablet of any one of E1 to E97.

E122. A method for treating a human subject with iron overload,comprising orally administering to the subject in need thereof 1200mg/day deferiprone, wherein the subject is administered the deferipronetwo times per day.

E123. The method according to E122, wherein the subject suffers from aneurogenic disease.

E124. The method according to E122 or E123, wherein the 1200 mg/daydeferiprone is administered at a dose of 600 mg two times a day.

E125. The method according to any one of E122 or E124, wherein the 1200mg/day deferiprone is administered at a dose of 1200 mg one time perday.

E126. The method according to any one of E122 to E125, wherein thesubject exhibits a C_(max) of 4.00 to 13.558 μg/mL after administrationof 600 mg deferiprone in the fed state.

E127. The method according to any one of E122 to E126, wherein thesubject exhibits a C_(max) of 5.880 to 13.690 μg/mL after 600 mgdeferiprone in the fasted state.

E128. The method according to any one of E122 to E127, wherein thesubject exhibits a T_(max) of 1.333 to 8.000 hours after administrationof 1200 mg deferiprone.

E129. The method according to any one of E122 to E128, wherein thesubject exhibits a AUCI/C_(max) of 3.265 to 6.765 hr afteradministration of 1200 mg deferiprone.

E130. The method according to any one of E122 to E129, wherein thesubject suffers from transfusional iron overload and whose priorchelation therapy is inadequate.

E131. The method according to any one of E122 to E129, wherein thesubject suffers from transfusional iron overload and has a cardiac MMT2* of 20 ms of less.

E132. The method according to any one of E122 to E131, wherein thesubject is administered a tablet of any one of E1 to E97.

E133. A tablet for oral administration comprising: (a) a core comprising1000 mg or 600 mg of deferiprone, an enteric polymer, a pH adjustingagent, a glidant, and a lubricant; and (b) an enteric coating comprisinga plasticizer, a diluent, an anti-tacking agent, and an enteric polymer,wherein the tablet is suitable for twice daily dosing, the tablet beinga whole tablet which is scored to facilitate breakage of the tablet intohalf tablets.

What is claimed is:
 1. A method for reducing gastric distress or therisk of gastric distress in a patient in need of deferiprone treatment,comprising orally administering to the patient a tablet comprising (a) acore comprising about 1000 mg deferiprone and an enteric polymer; and(b) an enteric coating comprising an enteric polymer, wherein the tabletis suitable for twice daily dosing.
 2. The method of claim 1, whereinthe enteric coating is about 0.5% to about 20% of the total weight ofthe tablet.
 3. The method of claim 2, wherein the enteric coating isabout 1% to about 10% of the total weight of the tablet.
 4. The methodof claim 2, wherein the enteric coating is about 0.5% to about 5% of thetotal weight of the tablet.
 5. The method of claim 1, wherein theenteric polymer in the coating is about 0.5% to about 4% by weight ofthe tablet.
 6. The method of claim 5, wherein the enteric polymer in thecoating is about 1% to about 2% by weight of the tablet.
 7. The methodof claim 5, wherein the enteric polymer in the coating is about 0.5% toabout 1% by weight of the tablet.
 8. The method of claim 1, wherein theenteric coating comprises about 5 mg to about 30 mg of an entericpolymer.
 9. The method of claim 8, wherein the enteric coating comprisesabout 7 mg to about 20 mg of an enteric polymer.
 10. The method of claim8, wherein the enteric coating comprises about 8 mg to about 15 mg of anenteric polymer.
 11. The method of claim 1, wherein the deferiprone isabout 75% to about 95% of the total core weight.
 12. The method of claim11, wherein the deferiprone is about 80% to about 95% of the total coreweight.
 13. The method of claim 11, wherein the deferiprone is about 85%to about 95% of the total core weight.
 14. The method of claim 1,wherein the core further comprises a basic excipient.
 15. The method ofclaim 14, wherein the basic excipient is about 1% to about 10% of thetotal weight of the core.
 16. The method of claim 15, wherein the basicexcipient is about 1% to about 5% of the total weight of the core. 17.The method of claim 1, wherein the core further comprises a lubricant.18. The method of claim 17, wherein the core comprises about 2 mg toabout 25 mg of the lubricant.
 19. The method of claim 18, wherein thecore comprises about 2 mg to about 10 mg of the lubricant.
 20. Themethod of claim 18, wherein the core comprises about 10 mg to about 20mg of the lubricant.
 21. The method of claim 1, wherein the entericpolymer is about 1.0% to about 5.0% of the total weight of the core. 22.The method of claim 1, wherein the enteric polymer is about 2.0% toabout 4.0% of the total weight of the core.
 23. The method of claim 1,wherein the enteric polymer is about 2.5% of the total weight of thecore.
 24. The method of claim 1, wherein the gastric distress is reducedas compared to orally administering to the patient an immediate releasedeferiprone tablet.